CN103533938A - 2,4 substituted pyrimidinediamines for use in discoid lupus - Google Patents

Abstract

Compounds I and II as well as salts and pharmaceutical compositions containing them are useful for treating diseases and/or disorders of the skin, such cutaneous lupus, for example acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, or discoid lupus erythematosus. In certain embodiments, the compounds are provided in topical compositions.

Description

For 2,4 thonzylamine that replace that use at discoid lupus

The cross reference of related application

The application requires the rights and interests of the U.S. Provisional Application submitted on March 10th, 2011 number 61/451,531, and it is combined in to this in full with it.

Field

The pharmaceutical composition that this disclosure relates to compound, its prodrug, salt and comprises them, and the method for using these compounds, its prodrug and the imbalance of compositions treatment Dermatology, these Dermatology imbalances are for example skin collagen angiopathys, for example, as cutaneous lupus imbalance, discoid lupus erythematosus.

Background

Jak kinase (JAnus kinases) is a cytoplasm protein family tyrosine kinase, comprises JAK1, JAK2, JAK3 and TYK2.Although multiple jak kinase can be subject to the impact of concrete cytokine or signal path, every kind of jak kinase selectivity is for the receptor of some cytokine.Research shows that JAK3 is associated with common gamma (γ c) chain of different cytokines receptor.Particularly, JAK3 is optionally bonded to receptor and is a part for the cytokine signaling path of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.The acceptor interaction of JAK1 and cytokine IL-2, IL-4, IL-7, IL-9 and IL-21 in addition, and the acceptor interaction of JAK2 and IL-9 and TNF-α in addition.When some cytokine (for example, IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21) while being bonded to its receptor, there is receptor oligomerization, cause the kytoplasm tail of the jak kinase that is associated to enter the state of approaching and promote the trans phosphorylation of the tyrosine residue on jak kinase.This trans phosphorylation causes the activation of jak kinase.

The jak kinase of phosphorylation is in conjunction with different STAT(signal transducer and activator of transcription) albumen.Stat protein (by the DBP of the phosphorylation activation of tyrosine residue) works as signaling molecule and transcription factor, and is finally bonded to the specific dna sequence of the promoter that is present in cytokine response gene.In many abnormal immune reactions, for example allergy, asthma, autoimmune disease (for example graft (allograft) repulsion, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis), in the mediation of ocular disorders and disease, together with solid malignant and hematologic malignancies, for example, in leukemia and lymphoma, involved JAK/STAT signal transduction.

Connective tissue disorder is one group of disease that affects the organ of broad variety, and is sometimes called as collagen vascular diseases.This class disease comprises the inflammatory imbalance of many uniquenesses, for example vasculitis, discoid lupus erythematosus (DLE), systemic lupus erythematosus (sle) (SLE), progressive systemic sclerosis, polymyositis/dermatomyositis, polymyalgia rheumatica, polyarteritis nodosa and Wei Genashi granulomatosis (Wegener's granulomatosis).In order to diagnose, the object of prognosis and treatment, these are by unique disease of difference mutually clinically.

Lupus erythematosus is a kind of disease that comprises the general category of systematicness imbalance and cutaneous disorder.The systemic form of this disease can have cutaneous manifestations and show together with systematicness.Yet it is only dermatosis and there is no the form of system pathological changes that this disease also exists.For example, SLE is a kind of inflammatory imbalance that mainly betides women, etiology the unknown, and be characterised in that joint symptom, butterfly erythema, recurrence pleuritis, pericarditis, extensive adenopathy, splenomegaly, together with CNS(central nervous system) pathological changes and carrying out property renal failure.The serum of Most patients (surpassing 98%) comprises antinuclear antibody (comprising Anti-DNA antibody).The Anti-DNA antibody of high-titer be substantially specificity for SLE's.The existing conventional therapy for this disease is giving of corticosteroid or immunosuppressant.

There is the cutaneous lupus of three kinds of forms: chronic skin lupus (also referred to as discoid lupus erythematosus or DLE), subacute cutaneous lupus and acute skin lupus.DLE is a kind of mainly by the next cutaneous chronic disproportion that diminishes profile of limitation macule and speckle sharp, and these limitation macules and speckle show erythema, follicular plug (follicular plugging), squama, telangiectasis and atrophy.This disease is normally precipitated by sun exposure, and these earlier damages be erythema, circle squamous papule, the diameter of these squamous papules is 5mm to 10mm and shows follicular plug.DLE damage appears at buccal, nose, scalp and ear the most commonly, and they can also the extensive top to trunk, on the mucosa on the extensor surface of extremity and oral cavity.If do not treated, the damage atrophy of these central authorities and stay next cicatrix.Different from DLE, for example, for the antibody of double-stranded DNA (, DNA-in conjunction with test) is almost unalterable in DLE, do not exist.

Conventional DLE therapeutic agent has comprised topical corticosteroid ointment or emulsifiable paste, for example triamcinolone acetonide, fluocinolone acetonide, flurandrenolide, betamethasone valerate or betamethasone dipropionate.Can use Intradermal steroid injection resistance speckle.Yet, continue to use corticosteroid itself can cause serious side effect, for example atrophoderma, texture, the easy injury with blood-stasis of skin and tear, dermatitis, telangiectasis and to infecting the susceptibility increasing.Other potential DLE therapeutic agent comprises calcineurin inhibitors, for example pimecrolimus emulsifiable paste or tacrolimus ointment.The case of special resistance can be treated with systemic antimalarial agent, for example hydroxychloroquine (PLAQUENIL).Yet this medicine is with the significant retinotoxic risk of the eye retina pathological changes of bull.Even after stopping this medicine, visual loss still can continue and not yet find to reverse the medical therapy of this retina injury.

DLE is a kind of disease that diminishes profile, for its current therapy, has been proved to be unsatisfactory.For other skin forms of lupus, for example acute and subacute form also needs treatment.

Summary of the invention

Understand now the compound of modulation JAK path and use the method for these compounds can be used for for example, providing treatment benefit for the experimenter of the lupus erythematosus (discoid lupus erythematosus (DLE)) of suffering from skin form.These compounds can by general give also or partly to give, but in instantiation, these compounds are directly applied to targeting skin injury, for example, with a kind of form of local preparation.In certain embodiments, this experimenter suffers from lupus erythematosus,cutaneous, for example DLE, subacute cutaneous lupus or acute skin lupus.In other examples, this experimenter only suffers from lupus erythematosus,cutaneous, for example DLE, subacute cutaneous lupus or acute skin lupus, and there is no any systematicness performance of lupus.Still in other embodiments, this medicine is used to the cutaneous manifestations of the lupus erythematosus (DILE) of medicine induction.

Disclosed compound, prodrug, corresponding salt form, and the method for using the cutaneous manifestations of these compounds, prodrug and salt form treatment lupus erythematosus,cutaneous (for example chronic skin lupus erythematosus (for example DLE)) or DILE.

An embodiment provides Compound I, and solvate, prodrug and pharmaceutically acceptable salt:

Another embodiment provides a kind of concrete prodrug and the pharmaceutically acceptable salt form thereof of Compound I, i.e. Compound I I:

In one aspect, with the Compound I of an effective dose and/or Compound I I, for example, together with its salt form with comprise that the pharmaceutical composition of this compound or these compounds treats this lupus erythematosus,cutaneous, DLE.It is a kind of by give effectively to treat the Compound I of amount of this disease and/or the method that Compound I I treats this lupus erythematosus,cutaneous to this experimenter that embodiment provides.In instantiation, this Pharmaceutical composition is directly given to one or more skin injurys by the form with a kind of local preparation, for example for example, damage on skin or mucosa (on oral mucosa).In instantiation, this part preparation is applied directly to this skin injury, and it is not used to reach any real mass of impregnable skin.

In aspect of disclosed method, one or more are at present disclosed 2,4-pyrimidinediamine compounds to give for the disappearing at least partly of damage that causes characterizing this disease be effective.In some instances, first this experimenter is confirmed as suffering from chronic skin lupus erythematosus (for example DLE), and does not suffer from SLE.For example, this experimenter shows Clinical symptoms and the Histopathological Characteristics of DLE, but does not have anti-double-stranded-DNA antibody.In other embodiments, this experimenter can suffer from DLE and SLE.

In one aspect of the method, compound or its pharmaceutically acceptable salt form with Formula I and/or Formulae II are given separately, also or for example, for example, with a kind of anti-inflammatory agent, antihistaminic, antibiotic, antiviral agent, softening agent or analgesics (topical pain relief agent (anesthetis or capsacinoid)) jointly or auxiliarily give.In instantiation, by general, given (for example orally or the intestines and stomach other places) also or part (for example give, with the form of emulsifiable paste or ointment, or be for example positioned at, on adhesiveness local application device (patch or adhesive tape)) antiinflammatory can be a kind of non-steroidal anti-inflammatory agent (NSAID) or corticosteroid (for example prednisolone), immunosuppressant (for example Ciclosporin A), counter-stimulus (for example Camphora) or pruritus (for example crotamiton).Alternately, the compound with Formula I and/or Formulae II is given separately, or with the form of local sunscreen, gives (for the ultraviolet exposure to conventionally making DLE worsen is minimized) with another kind of bioactivator.Still other combined therapies can comprise therapeutic alliance or the auxiliary treatment of using the Dermatology imbalance being associated, for example, in order to reduce laser therapy or the light exposure treatment of face red spot.

Typically, when for example, for topical treatment of skin lupus (DLE), the disclosed compound with Formula I and/or Formulae II at least gives once (for example every day at least twice, three times or four times) every day, or for example, for example, with a kind of slow release specification (a kind of adhesiveness allotter, patch) application to skin.

In another embodiment, the invention provides a kind of medicament preparation, this medicament preparation in parent form also or the Compound I of salt form and/or Compound I I comprises, and at least one pharmaceutically acceptable excipient, diluent, antiseptic, stabilizing agent or its mixture.

These and other embodiment have been described in more detail below.

Brief Description Of Drawings

Fig. 1 is a photos, this photo illustration when DLE appears at extremity, its some diminish the damage of profile.

Fig. 2 is a photos, this photo illustration plate-like cicatrix and the hypopigmentation on an experimenter's the occipital bone region of head.

Fig. 3 is a photos, this photo illustration by using the effect of the atrophoderma of local glucocorticoid.

Fig. 4 is a table, and this table illustrates the active and infringement of DLE skin injury, and the seriousness of the how to evaluate DLE that demonstrated.Such evaluation disease activity below and evaluating being useful in the response for the treatment of.

Abbreviation

ACLE: ACLE

CCLE: chronic skin lupus erythematosus

COX: cyclooxygenase

DES: dry eye syndrome

DILE: Drug lupus erythematosus

DLE: discoid lupus erythematosus

LE: lupus erythematosus

SCLE: subacute cutaneous lupus erythema tosus

SLE: systemic lupus erythematosus (sle)

STAT: signal transducer and activator of transcription

Describe in detail

Definition

As used herein, except as otherwise noted, should use following definition.

" corticosteroid " is the steroid hormone resulting from adrenal cortex.At the physiological system of broad range, for example, in the immunoreation of stress, inflammation and adjusting, carbohydrate metabolism, protein catabolism, electrolyte balance level and behavior, relate to corticosteroid.The example of corticosteroid comprises hydrocortisone, prednisone and prednisolone.Corticosteroid can orally give, parenteral gives (for example by injection), also or by being directly locally applied to the damage on skin, and they can with there is Formula I and/or Formulae II compound and merge in formulated in combination product." topical corticosteroid " is directly locally applied to skin, but life-time service topical corticosteroid causes ugly atrophoderma.

" skin " or " corium " refers to that skin, skin are the tissues that forms the outer cover of vertebrates health.Skin (being also sometimes referred to as " integumentary system ") is combined the impact that help protection health is avoided its external environment condition with mucosa (oral cavity, nasal cavity, oral cavity and eyelid film specifically).Skin is by two-layer composition (corium and epidermis), and in many animals (comprising the mankind), the outermost layer of skin is covered by hair at least partly.It is protection and sensation together with the major function of the mucosa in eyes, nose and oral cavity.

" cutaneous lupus " or " lupus erythematosus,cutaneous " refers to according to the cutaneous manifestations of the lupus erythematosus of the dermopathic Terry Gilliam classification of lupus erythematosus (Gilliam classification).Rothfield(Rosfeld) people such as, Clinics in Dermatology(" dermatology is clinical ") 24:348-362 (2006).This system is divided into specificity lupus erythematosus dermatosis and non-specific lupus erythematosus dermatosis by lupus dermatosis, and both illustrate distinguished histology and change.

" discoid lupus erythematosus " or " DLE " (being also referred to as chronic skin lupus erythematosus or CCLE) is a kind of chronic disproportion that conventionally diminishes profile that carrys out major effect skin by limitation macule and speckle sharp, and these limitation macules and speckle show erythema, follicular plug, squama, telangiectasis and atrophy.This disease is normally precipitated by sun exposure, and these earlier damages be erythema, circle squamous papule, the diameter of these squamous papules is 5mm to 10mm and shows follicular plug.DLE damage appears at buccal, nose, scalp and ear the most commonly, and they can also the extensive top to trunk, on the mucosa on the extensor surface of extremity and oral cavity.Different from SLE, for example, for the antibody of double-stranded DNA (, DNA-in conjunction with test) is almost unalterable in DLE, do not exist.In some embodiment in this disclosed method, can treat the negative DLE experimenter of double-stranded DNA (ds-DNA) with the compound with Formula I and Formulae II.

" chronic skin lupus erythematosus " (CCLE) is subdivided into classical discoid lupus erythematosus (DLE), child's discoid lupus erythematosus, extensive discoid lupus erythematosus, limitation discoid lupus erythematosus, lupus erythematosus profundus, lupus erythematosus panniculitis (lupus erythematosus profundus), erythroplakia lupus, lupus erythematosus tumidus, chilblain lupus erythematosus, lupus erythematosus lichen planus overlap syndrome, excipuliform lupus erythematosus (hypertrophic lupus erythematosus) and other rare mutation conventionally.Classical DLE is the most common form of CCLE, and major part suffers from the feature that the patient of classical DLE damage will never development system lupus erythematosus.Classical DLE be rendered as have epidermis squama well-defined red-pimple of purpura rash.The size of damage increases to the Hyperpigmented coin-shaped of periphery or plate-like speckle.Adhesiveness squama expands to the hair follicle of expansion.The central authorities of damage become flat along with scarring, the depigmentation and telangiectasis.These specklees can merge to form the large damage that diminishes profile.Hair follicle can be stopped up by thick squama, when being stripped from, demonstrates keratosis projection, and this projection is called as covering adhesiveness sign (carpet tack sign).Histopathological Characteristics comprises hyperkeratosis and follicular plug, organizes the spinous layer of forfeiture and the atrophy of substrate epidermis.Bottom can also show the painted and incontinence of pigment (pigment incontinence) of the melanin of edema, liquefaction, basement membrane thickened, increase.In corium, found the lymphocytic mononuclear cell penetrant of macrophage and T, wherein the plasma cell in chronic injury causes mucin deposition.

" drug-induced lupus erythematosus " is (DILE) as the side effect of life-time service some drugs and the different autoimmune disease occurring.The symptom of DILE is similar to those of SLE, and can comprise fatigue, low grade fever, inappetence, myalgia, arthritis, oral cavity and nasal cavity ulcer, facial rash, to the uncommon sensitivity of sunlight, pleuritis, pericarditis and Raynaud phenomenon (Raynaud ' s phenomenon).Ulcer and erythra are the examples of the cutaneous manifestations of DILE.After this pathogenic medicine of stopping using, these symptoms of patient disappear within a couple of days to several months, and this patient does not have potential immune system dysfunction.Causing the Common drugs of DILE is hydralazine, procainamide, quinidine, isoniazid, diltiazem and minocycline.Some these class medicines (for example procainamide, chlorpromazine and quinidine) cause the generation for the antinuclear antibody of histone dimer H2A-H2B.Hydralazine forms the antinuclear antibody of H1 and H3-H4 complex.DILE appears at several months of bringing into use after medicine conventionally to the several years, and by contrast, a few hours that the breaking into of SLE brought into use after medicine are now to a couple of days.

A patient for example, with one or more SLE clinical symptoms (, arthralgia, lymphadenopathy, erythra, heating) has been carried out to the diagnosis of DILE; There is antinuclear antibody; This patient did not have SLE history before using this pathogenic medicine; Before these symptoms occur, suspicious medicine has been taken 3 thoughtful 2 years unlimitedly; And when this medicine is stopped using, clinical improvements is rapidly, and antinuclear antibody and other serologic marker things reduce to more normal level lentamente.

" epithelial surface " refers to the tissue being comprised of the epithelial cell that covers body surface.Epithelial surface comprises the mucosa of outer surface (for example skin) and oral cavity and nasal cavity, together with inner body surface inside." outside " epithelial surface be exposed to body surface (for example skin and nasal cavity and oral cavity are inside) and for do not use instrument (for example endoscope or dissecting knife) to directly using of this surperficial emulsifiable paste or ointment be come-at-able those.

" lupus erythematosus " is (LE) generic term of a collection of autoimmune disease.The symptom of LE can affect different body systems, comprises joint, skin, kidney, hemocyte, heart and lung.LE can be shown as systemic disease (having skin and other performances) or be shown as pure dermatosis (only affecting skin).The systemic form of LE is called as systemic lupus erythematosus (sle) (SLE).Wherein, the skin form of LE is ACLE, subacute cutaneous lupus erythema tosus and chronic skin lupus erythematosus (discussed above, discoid lupus).

ACLE (ACLE) can be also circumscribed or extensive.Limitation ACLE is characterised in that facial cheekbone protuberantia and the erythema (butterfly bluss) on the bridge of the nose, and nasolabial fold is escaped by luck typically.Although the case of especially severe can produce blister epidermolysis (vesiculobullous) change of skin, the surperficial squama that ACLE erythra can have and being associated with edema.Histopathology changes focal liquefactive degeneration and the upper corium erythema that comprises rare hypodermal cell penetrant, substrate epidermis.Epidermal necrosis can occur with the most serious form.

Subacute cutaneous lupus erythema tosus (SCLE) is subdivided into two morphology mutation: annular SCLE and pimple squama SCLE.Annular SCLE is also referred to as tool edge lupus (lupus marginatus), the symmetrical erythema of centrifugal property, autoimmunity erythema iris and erythema gyratum serpens lupus (lupus erythematosus gyratum repens).SCLE is rendered as erythema speckle and pimple, and these speckles and pimple develop into pimple squama or annular speckle subsequently.Although some patients show both key elements simultaneously, most of patient trends towards main development becomes the damage of a type.SCLE is that non-ordinary light is quick, and wherein damage is most commonly in extensor surface and the back of the hand of cervical region and upper breast, upper back, shoulder, arm and forearm.Rarely relate to face and scalp.Histopathological Characteristics comprises the joint of hyperkeratosis, degeneration and corium-epidermis of basal cell layer and the mononuclear cell penetrant in corium.

" mucosa " (" mucous membranes " or " mucosa ") be absorb and secretion in relate to be mainly entoderm origin, be covered in epithelium inside.They align the chamber that is exposed to external environment condition and internal.They are in some positions, and for example nostril, oral cavity, lip, eyelid, ear, genital area and anus and skin continue.

" non-steroidal anti-inflammatory agent " is (NSAID) that a class is carried out the antiinflammatory of work by suppressing the generation of prostaglandins.NSAID brings into play antiinflammatory, pain relieving and antipyretic effect.The example of NSAID comprises ibuprofen, ketoprofen, piroxicam, naproxen, sulindac, aspirin, alkali formula choline salicylate, diflunisal, fenoprofen, indomethacin, meclofenamic acid, salsalate, tolmetin and magnesium salicylate.These medicaments can orally give, parenteral gives (for example by injection), also or by being directly locally applied to inflamed areas, and they can with there is Formula I and/or Formulae II compound and merge in formulated in combination product.

" pharmaceutically acceptable salt " refers to the biocompatibility salt of the compound that can be used as medicine, and these salt are derived from multiple organic and inorganic counterion well known in the art.

" pharmacy effective dose " or " treatment effective dose " refers to the specific imbalance of enough treatments or disease or its one or more symptoms and/or enough prevents this disease or the amount of imbalance generation." treatment " comprise stop the further developing of disease, together with reversing this imbalance (comprising disappearing of damage), or cure in some instances this imbalance.

As used herein, phrase " significantly reducing DLE damages " for example means, as passed through statistically (p < 0.05) minimizing significantly of the DLE damage of standard Dermatology practice measurement.The total surface area of one or more damages of the number of the damage that for example, the minimizing of DLE can be treated by counting or counting treatment is assessed.

" experimenter " refers to the mankind or non-human experimenter.

" systemic lupus erythematosus (sle) " or " SLE " is a kind of inflammatory Autoimmune Disorders that mainly betides women, and be characterised in that in many aspects joint symptom, butterfly erythema, recurrence pleuritis, pericarditis, extensive adenopathy, splenomegaly, together with CNS pathological changes and carrying out property renal failure.The serum of Most patients (surpassing 98%) comprises antinuclear antibody (comprising Anti-DNA antibody).The Anti-DNA antibody of high-titer be substantially specificity for SLE's.

" part " sent and referred to the cutaneous manifestations of a kind of preparation application to skin that comprises medicine directly being treated to cutaneous disorder or disease, is intended to instruct in fact this medicine to the pharmacological effect in the surface of skin or skin.Topical formulations is semi-solid systems typically, but can comprise multiple other dosage forms, for example foam, spray, pastille powder, solution and pastille viscosity system.Local delivery comprises is sent out, is sprayed or is dispersed on skin histology to cover the inside topical agent in affected region in other mode, or is administered to oral mucosa, vaginal mucosa or is applied to the structural inner topical agent of anal orifice and rectal intestine for Topically active.In this disclosed topical remedy, can give with any topical formulations, for example, as solid (powder, aerosol or plaster); Liquid (lotion, liniment, solution, Emulsion, suspension, aerosol) or semi-solid (ointment, emulsifiable paste, paste, gel, jelly or suppository).

Compound

Disclosed compound, prodrug, corresponding salt form, and used for example DLE of these compounds, prodrug and salt form treatment skin LE() method.

Described Compound I and Compound I I in more detail below, together with its salt form and the pharmaceutical composition that comprises them.Compound I is also referred to as N2-(3-amino-sulfonyl-4-tolyl) the fluoro-N4-[4-of-5-(Propargyl oxygen base) phenyl]-2,4-thonzylamine.Compound I I is also referred to as the fluoro-N2-of 5-(4-methyl-3-propionamido sulfonyl phenyl)-N4-[4-(Propargyl oxygen base) phenyl]-2,4-thonzylamine.

For the object of interest of clarity, any embodiment definitely being mentioned for Compound I and Compound I I, this embodiment also comprises the pharmaceutical composition that uses salt form and/or inclusion compound I and/or Compound I I.

Those of ordinary skill in the art will understand, and Compound I I is a kind of prodrug of Compound I, and Compound I I need not pharmacology upper deactivation until be converted into Compound I.The mechanism of base (progroup) metabolism is non-criticality before propiono, and can such as the hydrolysis under the acid condition by stomach and/or by be present in the digestive tract of health and/or the enzyme in tissue or organ (such as the Cytochrome P450 of esterase, amidase, lipase, phosphate (comprising ATP enzyme and kinases), liver, etc.) cause.In specific embodiment described herein, Compound I and/or Compound I I are used to treat Dermatology or cutaneous disorder (for example DLE), and therefore can directly to skin, be given.If what give is a kind of prodrug of deactivation, it can for example, be activated by the enzyme in skin (esterase), or reagent (for example, the deposit of the activated material in patch, or the additive mixing with prodrug before the local application) part of coming together that it can activate this medicine with another kind gives.In certain embodiments, give not only to comprise that part gives, can also comprise injection etc., for example intradermal injection or intralesional injection.Alternately, these activating agents can be given capapie.

Those of ordinary skill in the art will understand, and Compound I and Compound I I can show tautomerism, conformational isomerism and/or geometric isomerism.Should be understood that the present invention contains any tautomerism of these compounds, conformational isomerism and/or geometrical isomerism form together with the mixture of these multiple different isomerization bodily form formulas.Atropisomer is the stereoisomer producing because of the suffocate spin around singly-bound, and wherein the obstacle of rotation is enough high to allow the segregation (Eliel, the E.L. of E.L.(Erie) of these conformers; Wilen, S.H.(dimension human relations S.H.) Stereochemistry of Organic Compounds(" spatial chemistry of organic compound "); Wiley& Sons(Willie father and son publishing house): New York(New York), 1994; Chapter14(the 14th chapter)).Atropisomerism is significant, because it has introduced chiral element in the situation that there is no three-dimensional atom.The present invention is for example intended to contain and is attached to the Finite rotation of the key between the group on it around 2,4-thonzylamine core texture and its, or for example around sulfonamide and its, is attached to the atropisomer in the situation of Finite rotation of the key between the phenyl ring on it.Compound I and Compound I I can be in salt forms.This type of salt comprises and be applicable to medicinal salt (" pharmaceutically acceptable salt "), be applicable to salt for animals, etc.As known in the art, this type of salt can be derived from acid or alkali.Exemplary salt described herein is sodium salt, potassium salt, arginine salt, choline salt and calcium salt, and can use usually any pharmaceutically acceptable salt for method described herein.Because Compound I and Compound I I have basic group (for example pyrimidine nitrogen) and acidic-group (for example N2 of thonzylamine system and the sulfonamide on N4 and/or nitrogen) both, so these compounds can form pharmaceutically acceptable acid-addition salts or base addition salts.

In one embodiment, this salt is pharmaceutically acceptable salt.Conventionally, pharmaceutically acceptable salt is substantially to retain one or more desirable pharmaceutically actives of parent compound and those salt that are applicable to giving to the mankind.Pharmaceutically acceptable salt comprises the acid-addition salts forming with mineral acid or organic acid.The mineral acid that be applicable to form pharmaceutically acceptable acid-addition salts comprises, by way of example rather than restriction, halogen acids (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulphuric acid, nitric acid, phosphoric acid, etc.The organic acid that is applicable to the pharmaceutically acceptable acid-addition salts of formation comprises, by way of example rather than restriction, acetic acid, trifluoroacetic acid, propanoic acid, caproic acid, cyclopentanepropanoiacid acid, glycolic, oxalic acid, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, Palmic acid, benzoic acid, 3-(4-hydroxy benzoyl) benzoic acid, cinnamic acid, mandelic acid, alkylsurfuric acid (for example, methanesulfonic acid, ethyl sulfonic acid, 1, 2-ethane-disulfonic acid, 2-ethylenehydrinsulfonic acid, Deng), aryl sulfonic acid (for example, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-LOMAR PWA EINECS 246-676-2, 4-toluenesulfonic acid, camphorsulfonic acid, Deng), 4-methyl bicycle [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-benzenpropanoic acid, trimethylace tonitric, butylacetic acid, lauryl sulphate acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, Deng.

Pharmaceutically acceptable salt also comprises that the acid proton that exists in the parent compound by metal ion (for example, alkali metal ion, alkaline-earth metal ions or aluminium ion) salt that forms while substituting, the salt forming during also or for example, with a kind of organic base (, ethanolamine, diethanolamine, triethanolamine, N-METHYL-ALPHA-L-GLUCOSAMINE, morpholine, piperidines, dimethylamine, diethylamine, triethylamine, ammonia, etc.) coordination.

As known in the art, the form that Compound I and Compound I I can also for example, in solvate (hydrate) and N-oxides together with its salt.

Method

The invention provides for disease and/or imbalance at treatment skin and/or mucosa, and in the damage that particularly DLE causes, use 2, pyrimidinediamine compounds I and Compound I I, its prodrug, salt and pharmaceutical composition that 4-replaces.Particularly, Compound I and Compound I I are given separately or are given with other medicament combinations.As described, Compound I and/or Compound I I can be used as parent and/or salt form gives, and can be used as its medicament preparation and give, and can comprise that for prodrug Compound I I is activated be the activator of Compound I.

As used herein, and as understand well in the art, " treatment " is a kind of for obtaining the approach of useful or desirable result (comprising clinical effectiveness).For purposes of the present invention, no matter be detectable or undetectable, useful or desirable result can comprise following one or more, but be not limited to this: the alleviating or alleviate of one or more symptoms, the reduction of disease (comprising a kind of disease) scope, stablizing (of disease (comprising disease), do not worsen) state, stop spreading of disease, delay or the slowing down of disease (comprising disease), progress, alleviation or the mitigation of disease (comprising disease, state), and alleviate (be no matter part or whole).Compound I and Compound I I(are at least as the source of Compound I) be virtuous, and therefore can carry out local giving (for example local or by being injected to skin or mucosa) with low-down dosage, therefore systemic untoward reaction is minimized.Think that this treatment also avoided the side effect for example, being caused by the treatment of standard more (corticosteroid), and because it is applied directly to affected region, be highly effective.

Compound I and Compound I I are the virtuous of jak kinase 1 and inhibitor optionally, and particularly JAK1/3-dependent cell factor signaling operability in T cell and B cell, and the Syk-dependent signals in macrophage, dendritic cell and B cell transduction.For example, Compound I has for respectively at the JAK3 of scope of 0.18 μ M and 0.14 μ M and half the maximum valid density (EC in the mensuration based on human cell of Syk (human cell based assay) ₅₀), and to other cytokines (IL-1 β and TNF α) or receptor tyrosine kinase (RTK) signal transduction have seldom or there is no activity, and be not the extensive inhibitor of cell proliferation.Compound I has selectivity especially for the cytokine signaling path that comprises JAK3.Result as this activity, these compounds can be used in multiple external, body or under in vitro background, be used for regulating or suppress jak kinase activity, the signal cascade that jak kinase plays a role therein amplifies, and is subject to this type of signal cascade to amplify the biologically affecting.For example, in one embodiment, in vitro or in body, these compounds can be used for for example, in almost any cell type (hematopoietic cell) of expressing jak kinase inhibition jak kinase.They can also be used to be adjusted in the signal transduction cascade that wherein jak kinase, particularly JAK3 play a role and amplify.This type of JAK-dependent signals transductory cascade amplification comprises, but be not limited to, the signal cascade that relates to the cytokine receptor of common gamma chain amplifies, for example, as IL-4, IL-7, IL-5, IL-9, IL-15 and IL-21, or IL-2, IL-4, IL-7, IL-9, IL-15 and the cascade of IL-21 receptor signal are amplified.These compounds can also be used to external ground or body regulates interiorly, and particularly suppress to be subject to this type of JAK-dependent signals transductory cascade to amplify cell effect or the biologically affecting.This type of cell effect or biologically include, but are not limited to: the T-cell proliferation of this CD23 rise (IL-4/ramos CD23upregulation) of IL-4/ Rameau, IL-2 mediation, etc.Importantly, these compounds can be used for suppressing in vivo jak kinase, as target be treatment or prevention all also or part by the treatment approach of the disease of the active mediation of jak kinase.This type of disease is called as " disease of jak kinase mediation ".

Although do not wish to be bound by theory, think that compound described herein is effective treatment of these cutaneous disorders because (at least partly) its JAK suppresses active.What by jak kinase (at least partly), mediated can comprise according to the example of the disease of these methods treatments or prevention disease and the imbalance of skin or mucosa, include, but are not limited to be present in skin LE(on skin and mucosa for example DLE, ACLE, SCLE or DILE) damage.Yet as the result of above-mentioned activity, although method described herein is oriented to the treatment of skin and mucosa imbalance, giving of these compounds and/or preparation can be with other treatment benefit, that is, and in its hetero-organization or organ of health.An embodiment is a kind of imbalance of skin or mucosa or method of disease (for example DLE, ACLE, SCLE or DILE) for the treatment of, and has wherein also realized secondary benefits.For example, DLE damage activating agent being applied on eyelid can also be served as following effective treatment: xerophthalmia, dry eye syndrome, uveitis, anaphylaxis conjunctivitis, glaucoma or (eyes) acne erythematosa.Dry eye syndrome (DES), being called again keratoconjunctivitis sicca (KCS), keratitis sicca, sjogren syndrome or xerophthalmia, is oculopathy a kind of mankind of being common in and some animals, that vaporized and caused by the tear film of the tear generation reducing or increase.Uveitis or iridocyclitis refer to the inflammation in the intermediate layer (" tunica uvea ") of eyes, and can reference in common usage and any inflammatory process of inside ofeye.Anaphylaxis conjunctivitis is owing to irritated conjunctiva (covering the film of white of the eye part) inflammation.Glaucoma refers to the one group of disease that affects optic nerve, and relates to a kind of feature mode loss retinal ganglial cells, that is, and and a class optic neuropathy.The important risk factor (higher than 22mmHg or 2.9kPa) of the intraocular pressure glaucoma development raising, and inflammatory process (for example uveitis) can cause this rising of intraocular pressure.

The disclosed treatment for DLE, ACLE, SCLE or DILE can also be treated the symptom of acne erythematosa, and acne erythematosa is a kind of chronic inflammatory disease (hypertrophic rosacea) that is characterised in that the face red spot that can also affect eyes and nose.

In one embodiment, Compound I and/or Compound I I are used for treating any above-mentioned disease of eye and/or imbalance, therapeutic alliance DLE.In one embodiment, Compound I and/or Compound I I adopt as salt form.In a specific embodiment, Compound I I is used as salt form.In one embodiment, the salt of Compound I I is selected from sodium salt, potassium salt, calcium salt, arginine salt and choline salt.

Give altogether

When being used for treating the damage of skin and/or mucosa, Compound I and Compound I I can give separately, as mixture, give and/or combine and give activating prodrug or the disease for the treatment of skin and/or the useful medicament of lacking of proper care with it.Compound I and Compound I I can with mixture give or with the useful medicament for the treatment of other diseases (disorder or malady) is combined and is given, these medicaments are for example, only lift several examples, steroid, membrane stabilizer, 5-lipoxygenase (5LO) inhibitor, leukotriene is synthesized and acceptor inhibitor, the conversion of IgE isotype or IgE synthetic inhibitor, the conversion of IgG isotype or IgG synthetic inhibitor, beta-2-agonists, tryptase inhibitors, aspirin, cyclooxygenase (COX) inhibitor, methotrexate, anti-TNF medicine, Rituximab, PD4 inhibitor, p38 inhibitor, PDE4 inhibitor, and antihistaminic.Compound I and Compound I I can itself, using prodrug forms or give as the pharmaceutical composition that comprises reactive compound and/or prodrug.

At these these disclosed pharmaceutical compositions, can give altogether with the other treatment of multiple application to skin (side by side or sequentially), for example antibacterial agent (for example Mupirocin Ointment or clindamycin); Antipsoriatic thing (for example Micanol); Antifungal (for example Terbinafine, clotrimazole and ketoconazole); Acne treatment (for example benzoyl peroxide topical formulations); Treatment (for example coal tar) for seborrheic dermatitis; Corticosteroid; Retinoid (for example retinoic acid and sieve skin lattice (Tazorac)), is used for treatment derived from vitamin A and comprises gel or the emulsifiable paste of disease of acne; And wart treatment (for example salicylic acid).Any these medicaments can provide with preparation a kind of part or beauty treatment, for example, for example, with lotion, ointment, emulsifiable paste, gel, soap, shampoo or adhesiveness applicator, patch.

At these these disclosed pharmaceutical compositions, can also give altogether with multiple other treatment (side by side or sequentially), these other treatments are application to skin not, the treatment that for example systematicness (for example orally or the intestines and stomach nonlocal) gives.The example of this type of systemic treatment comprises other anti-lupus medicines (hydroxychloroquine (PLAQUENIL) for example, corticosteroid (for example prednisone), antibiotic (erythromycin for example, tetracycline, and dicloxacillin), antifungal (for example ketoconazole and fluconazol), antiviral agent (valaciclovir for example, acyclovir, and famciclovir), corticosteroid, immunosuppressant (cyclophosphamide for example, azathioprine, methotrexate, mycophenolic acid), and biological agent (Rituximab for example, Embrel, adalimumab, infliximab, excellent spy gram monoclonal antibody, and the gene squama health of dispelling).

The concrete immunosuppressive therapy that can combine with Compound I and Compound I I use comprises, for example, purinethol, corticosteroid (prednisone for example, methylprednisolone and prednisolone), alkylating agent (for example cyclophosphamide), calcineurin inhibitors (ciclosporin for example, sirolimus and tacrolimus), imp dehydrogenase (IMPDH) inhibitor (mycophenolic acid for example, Mycophenolate Mofetil and azathioprine), and the medicament that is designed for the humoral immune reaction that suppresses the simultaneously complete reservation of cellular immunization receiver, comprise different antibodies, for example, antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibody (OKT3) and radiation.These different medicaments can according to as in the prescription information of commercially available form of following these medicines specified its standard or common dosage use (also referring to, doctor's desk reference ( the? physician ' s Desk Reference) versions in 2006 in prescription information), its disclosure content is combined in to this by reference.Azathioprine is obtainable at present from the brand name AZASAN of Salix drugmaker; Purinethol is obtainable at present from the brand name PURINETHOL of Gate drugmaker; Prednisone and prednisolone are obtainable from Roc coral laboratory company (Roxane Laboratories, Inc.) at present; Methylprednisolone is obtainable from Pfizer at present; Sirolimus (rapamycin) is obtainable at present from the brand name RAPAMUNE of Wyeth (Wyeth-Ayerst); Under the brand name PROGRAF of the current Cong Tengze of tacrolimus company (Fujisawa), be obtainable; Ciclosporin is obtainable at present from Novartis Co.,Ltd (Novartis) brand name cyclosporin A (SANDIMMUNE) and the brand name GENGRAF of Abbott (Abbott); IMPDH inhibitor (for example Mycophenolate Mofetil and mycophenolic acid) is obtainable at present from Roche Holding Ag (Roche) brand name MMF (CELLCEPT) Xia He Novartis Co.,Ltd (Novartis) the peaceful body health of brand name (MYFORTIC); The current Cong Gelansu Sino-U.S. of azathioprine SmithKline company (Glaxo Smith Kline) brand name is according to being obtainable under Drymotaenium miyoshianum (Mak.) Mak. (IMURAN); And antibody is at present from the brand name SIMULECT(of (Ortho Biotech) brand name ORTHOCLONE Xia, Novartis Co.,Ltd of Otto biotech company (Novartis) basiliximab) and the brand name ZENAPAX(of Roche Holding Ag (Roche) daclizumab) under be obtainable.

In one embodiment, there is the compound of Formula I and/or II or the ophthalmology preparation of its pharmaceutically acceptable salt form and a kind of medicine (for example antihistamine drug, antibiotic, anti-inflammatory drug, antiviral drugs or glaucoma medicine) jointly also or auxiliarily gives.This type of combination preparation for example, is useful especially for the case of the DLE of the skin (eyelid) for the treatment of major effect around eyes, and can around give to eyes or its, for example, with the form of drop or ointment.When preparation is during these formulated in combination product, have Formula I and/or II compound (comprising its pharmaceutically acceptable salt form) can with merge below: ophthalmology antibiotic (for example sulfacetamide, erythromycin, gentamycin, tobramycin, ciprofloxacin or ofloxacin); Ophthalmology corticosteroid (for example prednisolone, fluorometholone or dexamethasone); Ophthalmology non-steroidal anti-inflammatory agent (for example ibuprofen, diclofenac, ketorolac or flurbiprofen); Ophthalmology antihistaminic (for example levocabastine, olopatadine (patanol), sodium cromoglicate, A Lemai (alomide) or pheniramine); Ophthalmology antiviral agent medicament for the eyes (for example bent fluorothymidine (triflurthymidine), adenine, galactoside or idoxuridine); Ophthalmology glaucoma medicine (for example beta blocker, for example timolol, metipranolol, carteolol, betaxolol or levobunolol); Ophthalmology prostaglandin analogue (for example latanoprost); Ophthalmology cholinomimetic agonist (for example pilocarpine or carbachol); Ophthalmology alfa agonists (for example brimonidine (bromonidine) or A Pu clonidine (iopidine)); Ophthalmology carbonic anhydrase inhibitors (for example dorzolamide); And ophthalmology adrenaline excitant (for example epinephrine or dipivefrine).

Pharmaceutical composition

The pharmaceutical composition that comprises Compound I described herein and II can fly to prepare dragee (dragee-making levigating), emulsifying, encapsulated, trapping (entrapping) or freeze drying process by conventional mixing, dissolving, granulating, water and manufacture.These compositionss can be prepared with the upper acceptable carrier of one or more physiologys, diluent, excipient or auxiliary agent for a kind of usual manner, they assist reactive compound to the technique of preparation, these preparations can be medicinal, and (locally or topically) particularly partly.

As described in this, Compound I and II can itself or with hydrate, solvate, N-oxide or pharmaceutically acceptable salt form, be formulated in this pharmaceutical composition.Typically, this type of salt, than corresponding free bronsted lowry acids and bases bronsted lowry solution more soluble in water, still also can form the salt than the free bronsted lowry acids and bases bronsted lowry of correspondence with lower dissolubility.

In one embodiment, a kind of medicament preparation comprises Compound I and/or Compound I I and at least one pharmaceutically acceptable excipient, diluent, antiseptic or stabilizing agent or its mixture.

In one embodiment, as previously mentioned, these compounds are provided as nontoxic pharmaceutically acceptable salt.The applicable pharmaceutically acceptable salt of compound of the present invention comprises acid-addition salts, for example, with those of following formation: hydrochloric acid, fumaric acid, p-methyl benzenesulfonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.Amido salt can also comprise quaternary ammonium salt, and wherein amino nitrogen atom is carried an applicable organic group, for example alkyl, thiazolinyl, alkynyl or an aralkyl moiety.In addition, when these compounds described herein carry an acidic moiety, its applicable pharmaceutically acceptable salt can comprise slaine, for example alkali metal salt, for example sodium salt or potassium salt; And alkali salt, for example calcium salt or magnesium salt.

These pharmaceutically acceptable salts described herein can form by conventional means, for example, by a kind of solvent or medium (this salt is insoluble in this solvent or medium) or in a kind of solvent (for example, in a vacuum except the solvent that anhydrates), the free alkali form sour equivalent suitable with one or more of this product reacted, or by lyophilization, or on a kind of applicable ion exchange resin by being another kind of anion by a kind of anion exchange of existing salt.

Compound I and II can be by oral, parenteral (for example, intramuscular, endoperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by suction, spray, nasal cavity, vagina, rectum, Sublingual, urethra (for example, urethral bougie) or the local approach giving (for example, gel, ointment, emulsifiable paste, aerosol, Deng) give, and can be individually or be formulated in together in applicable dosage unit preparation, these dosage unit preparations comprise conventional nontoxic pharmaceutically acceptable carrier, adjuvant, excipient and the applicable various carriers that give approach.Except treatment homoiothermic animal (such as mice, rat, horse, cattle, sheep, Canis familiaris L., cat, monkey, etc.), these compounds described herein can be also effective in the mankind.

For giving the pharmaceutical composition of Compound I and II, can with dosage unit form, exist routinely, and can prepare by any method of knowing in pharmaceutical field.These pharmaceutical compositions can be for example by make active component equably and nearly with solid carrier or both combinations of a kind of liquid-carrier or fine dispersion, and then, if necessary, this product is shaped to desirable preparation and/or it is positioned in suitable packing and is prepared.In the local preparation of disclosed compound, this preparation is positioned in a suitable container and (for example has one for allocating the extruded tube of the lid of ointment and emulsifiable paste).Alternately, this allotter can comprise that one for example, for allocating the device (bottle or the dropper to target region by controlled pre-definite dose distribution of this medicine) of the unit dose of this medicine.This activity target compound is included in this pharmaceutical composition with an amount that enough produces desirable therapeutic effect.For example, pharmaceutical composition described herein can take any pattern that is applicable to giving almost (comprise such as part, eyes, oral, oral cavity, whole body, nasal cavity, injection, percutaneous, rectum, vagina, etc.) form, or take to be applicable to by sucking or be blown into the form giving.

As known in the art, for part, give, can by one or more JAK-optionally compound or prodrug be formulated as solution, gel, ointment, emulsifiable paste, suspension, etc.Except being applicable to giving to skin, these solution, gel, ointment, emulsifiable paste and suspension are also applicable to directly to eyes, giving very much.An embodiment is a kind of medicament preparation that comprises Compound I and/or Compound I I, and wherein this preparation is selected from a kind of solution, gel, ointment, emulsifiable paste and suspension.In one aspect, this type of preparation of preparing for part comprises Compound I and/or Compound I I or its pharmaceutically acceptable salt for the treatment of effective dose, for example, the in the situation that of Compound I, hydrochlorate or benzene sulfonate, and as an example, the lysinate of Compound I I, choline salt or arginine salt.The specific embodiment of the preparation using for method described herein comprises compound, local alkali, antioxidant, softening agent and the emulsifying agent of a treatment effective dose.Those of ordinary skill in the art will understand, and a treatment effective dose of compound can change, but typically, this treatment effective dose is from 0.1% to 10%(w/w).

Local alkali can comprise the Polyethylene Glycol of the selectable molecular weight of tool.Specific embodiment comprises as Polyethylene Glycol local alkali, that have from 3000 to 8000 daltonian molecular weight.

In certain embodiments, this preparation is a kind of ointment, and may further include a kind of water can intersolubility solvent, for example have from the poly alkylene glycol of the daltonian mean molecule quantity of 200 dalton to 600.In certain embodiments, this water can comprise PEG-400 by intersolubility solvent, and PEG-400 substantially free from foreign meter even more specifically.In certain embodiments, PEG-400 substantially free from foreign meter comprises and is less than the formaldehyde of 65ppm, the formaldehyde that is less than 10ppm or 1ppm or formaldehyde still less.

Local preparation for purposes described herein can also comprise a kind of penetration enhancers, for example isosorbide dimethyl ether, propylene glycol or its combination; , water for example; , for example sorbitan monostearate, polyethylene stearic acid ethylene glycol ester, D-alpha-tocopherol polyethylene glycol 1000 succinates, the compositions that comprises ethylene glycol amber acid esters/PEG32 succinate/PEG6 succinate and the combination of surfactant; , for example Butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, tocopherol and combination thereof, wherein specific embodiment comprises the butylated hydroxytoluene as antioxidant; And a kind of optional coloring agent, for example 0.05% to 0.25%(w/w) caramel color.

For specific embodiment, this treatment effective dose is from 0.1% to 10%(w/w), and this medicament preparation further comprises: from 15% to 40%(w/w) local alkali, for example there is the poly alkylene glycol of from 4000 to 5000 daltonian mean molecule quantities; From 25% to 50%(w/w) water can intersolubility solvent, for example there is the poly alkylene glycol of from 300 to 500 daltonian mean molecule quantities; From 10% to 20%(w/w) penetration enhancers, isosorbide dimethyl ether for example; From 3% to 15%(w/w) softening agent, water for example; From 3% to 9%(w/w) surfactant, polyethylene stearic acid ethylene glycol ester for example; And as antioxidant from 0.5% to 1.5%(w/w) butylated hydroxytoluene.

Another embodiment of this medicament preparation comprises from 0.2% to 6%(w/w) Compound I or its pharmaceutically acceptable salt; 30% to 40%(w/w) the Polyethylene Glycol with from 4000 to 5000 daltonian mean molecule quantities; From 30% to 40%(w/w) the Polyethylene Glycol with from 300 to 500 daltonian mean molecule quantities; Isosorbide dimethyl ether 15%(w/w); 3% to 5%(w/w) water; Polyethylene stearic acid ethylene glycol ester 5%(w/w); Butylated hydroxytoluene 1%(w/w); And 0.05% caramel.

Still another embodiment of this medicament preparation comprises 1%(w/w) Compound I; 25% to 40%(w/w) the Polyethylene Glycol with 4500 daltonian mean molecule quantities; And 30% to 45%(w/w) the Polyethylene Glycol with 400 daltonian mean molecule quantities.

Still another embodiment of this medicament preparation comprises 3%(w/w) Compound I; The Polyethylene Glycol with 4500 daltonian mean molecule quantities 32%(w/w); And 38% to 42%(w/w) the Polyethylene Glycol with 400 daltonian mean molecule quantities.

Still another embodiment of this medicament preparation comprises 6%(w/w) Compound I; The Polyethylene Glycol with 4500 daltonian mean molecule quantities 35%(w/w); And 33% to 35%(w/w) the Polyethylene Glycol with 400 daltonian mean molecule quantities.

In one embodiment, this preparation is a kind of solution.In another embodiment, this preparation is a kind of gel.In another embodiment, this preparation is a kind of suspension.Still in another embodiment, this preparation is a kind of emulsifiable paste or ointment.Embodiment is any above-mentioned preparation of the test kit that gives for local (topical or local).In one embodiment, this preparation is a kind of liquid of selling with bottle, the for example liquid of homogeneity or suspension, this bottle is assigned as drop or liquid film (for example, from the tip of an applicator, the target region of this tip contact skin is to be only distributed in this liquid on the target region of skin to be treated substantially) by this preparation.In one embodiment, this preparation is a kind of emulsifiable paste or ointment of selling with pipe, and this pipe is dispensed to this preparation the target region of skin.In another embodiment, this compound for example, is provided into viscous liquid (carboxymethyl cellulose, hydroxypropyl emthylcellulose, Polyethylene Glycol, glycerol, polyvinyl alcohol or the oil-containing drop) form of eyes for rubbing into skin or instiling with a kind of.These preparations can have antiseptic or preservative free (for example, in a kind of disposable use container).

For topical use, emulsifiable paste, ointment, jelly, gel, solution or suspension, etc., Compound I and II can be used for manufacturing a kind of compositions or medicament, comprise and are applicable to the medicament that part gives.In certain embodiments, Compound I and II and Polyethylene Glycol (PEG) can be prepared for part and given.These preparations can optionally comprise extra pharmaceutically acceptable composition, for example diluent, stabilizing agent and/or adjuvant.In specific embodiment, these local preparations are prepared to disease and/or the imbalance that is used for the treatment of skin, cutaneous lupus for example, for example, as chronic skin lupus, DLE.

Systematicness preparation is included as by injection, for example in subcutaneous, intravenous, intramuscular, sheath or endoperitoneal injection and design those, together with for percutaneous, wear mucosa oral or that pulmonary gives to design those.

Useful injectable preparation comprises sterile suspensions, solution or the emulsion of one or more reactive compounds in aqueous or oiliness carrier.These compositionss can also comprise preparaton, for example suspending agent, stabilizing agent and/or dispersant or for activating the activator of this prodrug.For these preparations of injecting, can exist with unit dosage forms, for example, at ampoule bottle or in multi-dose container, and can comprise the antiseptic of interpolation.They can also be provided in syringe, for example, have the syringe that this drug injection is entered to the syringe needle of skin (for example direct injection enters DLE damage).

Alternately, before using, this injectable preparation can be for being provided with a kind of powder type of applicable carrier rehydration, these carriers including, but not limited to aseptic apyrogeneity Free water, buffer agent, glucose solution, etc.This powder can comprise the activator for a kind of prodrug, and when this powder is dissolved in a kind of carrier, this activator activates this prodrug.For this object, this or these reactive compounds can be dried by any technology known in the art, for example lyophilization, and carried out rehydration before using.

For wearing mucosa, give, in this preparation, use the penetrating agent that is applicable to having obstacle to be infiltrated.This type of penetrating agent is known in this area, and comprises dimethyl sulfoxine (DMSO) and isosorbide dimethyl ether.Yet these penetrating agent can also be used to this to be improved these activating agents and enters sending of skin.

For oral, give, these pharmaceutical compositions can be taked following form: for example, for example, for example, by the pharmaceutically acceptable excipient of conventional means (sticky agent (pregelatinization corn starch, polyvinylpyrrolidone or hydroxypropyl emthylcellulose); Filler (for example lactose, microcrystalline Cellulose or calcium hydrogen phosphate); Lubricant (for example magnesium stearate, Talcum or silicon dioxide); Disintegrating agent (for example potato starch or sodium starch glycolate); Or wetting agent (for example sodium lauryl sulphate)) lozenge, tablet or the capsule prepared.These tablets can for example carry out coating with sugar, film or enteric coating by method well known in the art.Extraly, in being applicable to the pharmaceutical composition of the form that orally uses, can also comprise, for example, dragee, lozenge, suspension aqueous or oiliness, dispersible powder or granule, emulsion, hard capsule or soft capsule or syrup or elixir, these pharmaceutical compositions comprise as 2 of its active component or prodrug, the thonzylamine that 4-replaces.The compositions being intended to for orally using can be prepared according to any method for the manufacture of pharmaceutical composition known in the art, and for pharmaceutically exquisite and agreeable to the taste preparation is provided, such composition can comprise one or more reagent that is selected from lower group, and this group is comprised of the following: sweeting agent, flavoring agent, coloring agent and antiseptic.Tablet comprises the active component (comprising prodrug) with nontoxic pharmaceutically acceptable mixed with excipients, and these excipient are applicable to the manufacture of tablet.These excipient for example can be, inert diluent, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent (for example, corn starch or alginic acid); Sticky agent (for example starch, gelatin or arabic gum); And lubricant (for example magnesium stearate, stearic acid or Talcum).These tablets can be coatings not, or they can come coating to postpone disintegrate and the absorption in gastrointestinal tract by known technology, and at one, provide more over a long time lasting effect thus.For example, can adopt time delay material, for example glyceryl monostearate or distearin.They can also be by being described in U.S. Patent number 4,256, and the technology in 108,4,166,452 and 4,265,874 is carried out coating to be formed for the osmotic therapeutic tablets of controlled release.These pharmaceutical compositions described herein can also be in O/w emulsion form.

Can take following form for the oral liquid preparation giving: for example elixir, solution, syrup or suspension, or they can be used as a kind of water before use or other applicable carriers carry out the dry products of chemical combination and exist.This type of liquid formulations can for example, for example, by the pharmaceutically acceptable additive of conventional means (suspending agent (sorbitol syrups, cellulose derivative or hydrogenation edible fat); Emulsifying agent (for example lecithin or arabic gum); Non-aqueous carrier (for example almond oil, grease class, ethanol, cremophore ^tMor fractionated vegetable oil); And antiseptic (for example methyl parahydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid)) prepare.These preparations can also take the circumstances into consideration to comprise buffer salt, antiseptic, flavoring agent, coloring agent and sweeting agent.

As is well known, for the oral preparation giving, can compatibly prepare to provide the controlled release of this reactive compound or prodrug.

For buccal, give, these compositionss can be taked the tablet prepared in a usual manner or the form of lozenge.

For the rectum giving and vaginal approach, this or these reactive compounds can be formulated as solution (for enema,retention) suppository or the ointment that comprises conventional suppository bases (for example cocoa butter or other glyceride).

This or these reactive compounds or prodrug can use a kind of applicable propellant expediently from pressurized package or aerosol apparatus the form with spray be delivered, this propellant is for example dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, fluorocarbon, carbon dioxide or other applicable gas.When giving a kind of prodrug, it can be sent altogether thus and mix with a kind of activator, for example, for Compound I I is activated as Compound I.The in the situation that of pressurised aerosol, this dosage unit can be by providing one to determine for sending the valve of the amount of a metering.Can prepare capsule or cartridge case (capsule and the cartridge case that for example comprise gelatin) for using at an inhaler or insufflator, the mixture of powders that these capsules or cartridge case comprise this compound and a kind of applicable powder substrate (for example lactose or starch).

These pharmaceutical compositions can be in aseptic injectable aqueous or oily suspensions form.Those applicable dispersants that this suspension can have been mentioned above according to use known in the art or wetting agent and suspending agent are prepared.This aseptic injectable formulation can also be aseptic Injectable solution or the suspension in the acceptable diluent of a kind of nontoxic parenteral or solvent.In the acceptable carrier that can adopt and solvent, there are water, Ringer's mixture and isotonic sodium chlorrde solution.The form of the suppository that Compound I and II can also give for rectum or the urethra of this medicine gives.In specific embodiment, these compounds can be configured to urethral bougie, for example, for using in the treatment of fertility disease, particularly in male, for example, be used for the treatment of testicular function disorder.

According to the present invention, the pyrimidinediamine compounds that 2,4-replaces can, for the manufacture of a kind of compositions or medicament, comprise the medicament that applicable rectum or urethra give.The invention still further relates to for the manufacture of give the method for the compositions of form (comprising suppository) in being applicable to urethra or rectum, these compositionss comprise the pyrimidinediamine compounds that 2,4-replaces.

Be included in the device of the instantiation that can be used for giving Compound I and II be well known in the art those, for example, metered dose inhaler, liquid dispenser, Diskus, aerosol apparatus, foaming machine, hot vaporizer, etc.Other are concrete 2 for giving, and the applicable technology of the pyrimidinediamine compounds that 4-replaces comprises electrofluid nebulizer.Can use spray, aerosol, sponge point type applicator (sponge-tipped applicator) and foam dispenser that compound itself also or in preparation form is directly given to skin, or for example, give by the skin injury (DLE damage) that direct intradermal injection is entered LE.

Typically, the preparation giving for skin comprises the disclosed 2 at this of a pharmacy effective dose, 4-pyrimidinediamine compounds, for example from approximately 0.0001% to approximately 1.0% or more (w/w) by weight.In some preparation, the pharmacy effective dose of this compound is 0.0003% to about 0.1%(w/w), for example, from approximately 0.003% to about 0.5%(w/w) or from approximately 0.01% to about 0.03%(w/w).In other examples, this compound with at least 2%, 3% or 5%(w/w) exist.

In some instances, a kind ofly comprise 2 of current disclosure, 4-pyrimidinediamine compounds, the ophthalmic composition giving for eye comprise a kind of tonicity agent, buffer agent or both.In some example of ophthalmic composition, this tonicity agent is a kind of simple carbohydrate or sugar alcohol.As known to persons of ordinary skill in the art, in compositions of the present invention, can with tonicity agent, regulate the Zhang Du of said composition, be preferably adjusted to the Zhang Du of normal tear.The example of applicable tonicity agent includes, but are not limited to: sodium chloride; Potassium chloride; Magnesium chloride; Calcium chloride; Carbohydrate, glucose for example, fructose, galactose, polyhydric alcohol, for example sugar alcohol, comprises mannitol, sorbitol, xylitol, lactose, hydroxyl isomaltulose, maltose alcohol and combination thereof by way of example.In some instances, the compositions that comprises a kind of buffer agent comprises phosphate, citrate or both.

Described herein this or these 2, the pyrimidinediamine compounds that 4-replaces or prodrug or its compositions will be used with an amount that effectively realizes expected result conventionally, for example, with an effective amount for treatment or the concrete disease of preventing treating.This or these compounds can be treated to be achieved treatment benefit or prevention upper to the prevention benefit that is achieved.Elimination or the alleviation of the elimination of the basis imbalance that treatment benefit means treating or alleviation and/or one or more symptoms of being associated with this basis imbalance, although this patient may still be tormented by the imbalance of this basis, this patient report in sensation or disease improves.For example, to the patient who suffers from DLE, give a kind of compound, not only when this basic corium infringement is uprooted or alleviates, provide treatment benefit, and treatment benefit is also provided when this patient reports minimizing in the seriousness of the symptom being associated with DLE or on the persistent period.No matter in symptom, whether realized improvement, treatment benefit also comprises the stopping or slowing down of progress of this disease.

For prevention, give, this compound can be given to the patient in a risk in developing into one of above-mentioned disease.For example, if do not know that whether irritated patient to concrete medicine, can before giving this medicine, give this compound to avoid or to improve the anaphylaxis to this medicine.Alternately, can apply prevention to the outbreak of being avoided being diagnosed as the patient's who suffers from this basis imbalance symptom.For example, before expection is exposed to a kind of anaphylactogen, can give a kind of compound to anaphylaxis victim.In order to prevent the outbreak of imbalance, compound prophylactically can also be given to healthy individuals, these healthy individuals are exposed to the known medicament of one of above-mentioned disease repeatedly.For example, in order to stop body one by one to develop into anaphylaxis, can give a kind of compound to this healthy individuals, this healthy individuals is exposed to the anaphylactoid anaphylactogen in known induction eyes, for example pollen repeatedly.

The amount of the compound giving will depend on many factors, comprise bioavailability such as the concrete disease for the treatment of, the pattern giving, the seriousness of disease for the treatment of and this patient's age and body weight, concrete reactive compound, etc.Within definite well ability in those of ordinary skill in the art of effective dose.A skilled practitioner can determine the optimal dose for concrete individuality.Effective dose can be estimated at first from external test.For example, can prepare one for the predose that uses animal to realize concentration blood circulation or serum of reactive compound, this concentration in or higher than as measure in vitro the IC of this for example, in (external test of describing) measured particular compound in this example 3 and 4 ₅₀.Similarly, can prepare a predose for the prodrug that uses in animal general to realize concentration blood circulation or serum of metabolite reactive compound, this concentration in or higher than the IC of this particular compound in measuring in vitro ₅₀.Consider the bioavailability of this particular compound, calculate the dosage well within the ability in technical staff of realizing concentration such blood circulation or serum.In order to instruct, reader can be with reference to Fingl& Woodbury(Fu Yinggeer; Woodberry), " General Principles(General Principle) ",: Goodman and Gilman ' s The Pharmaceutical Basis of Therapeutics(" the treatment pharmacy basis that Gourde(G) is graceful and gill is graceful "), the 1st chapter, pp.1-46, latest edition, Pergamon Press(Pei Geman publishing company), and the reference paper of wherein quoting.

Can also use animal model (for example in example 9 disclose those) to go out predose from data estimation in body.It is well known in the art for test, being used for treating or preventing the useful animal model of curative effect of the compound of above-mentioned various disease.The dosage giving for general is by typically in from approximately 0.0001 or 0.001 or the scope of 0.01mg/kg/ days to about 100mg/kg/ days, but can be higher or lower, inter alia, the activity, its bioavailability, the pattern giving and the different factor discussed above that depend on this compound.Can regulate individually systemic doses and interval, to provide this or these compounds enough to maintain the blood plasma level of therapeutic effect or preventive effect.For example, these compounds can be once in a week, several times (for example, every other day), once a day or repeatedly give every day, inter alia, depend on the pattern giving, the specific adaptations disease for the treatment of and prescription doctor's judgement weekly.In part, give or for example, selectivity picked-up (local topical gives) in the situation that, effective local concentrations this or these reactive compounds can be not relevant with plasma concentration.Without excessive experiment, technical staff can the effective local dose of optimization.Higher therapeutic index far away in view of giving to local skin, can be increased to dosage to exceed general systemic doses, and side effect and toxicity are not needed to significant additional attention.

Technical staff is apparent to be recognized, about to 2, the above-mentioned disclosure that the dosage of the pyrimidinediamine compounds that 4-replaces requires relates to the dosage of prodrug needs, the amount of this or these prodrugs that give also will depend on many factors, comprise bioavailability such as this or these concrete prodrugs, under the approach that gives of selecting to the conversion ratio of active pharmaceutical compounds and curative effect, the activator giving altogether, etc.Within the ability in those of ordinary skill in the art of determining well for the effective dose of one or more prodrugs of concrete purposes and the pattern that gives.

For part or eye, give, effective dose can be by giving not cause those in the situation of significant systemic circulation of these compounds to skin or eyes, for example, before significant systemic circulation, local preparation is applied directly to skin injury and utilizes a very circumscribed dosage.

At this, Compound I in disclosed method and the extra compound of II have been expected definitely replacing, and be described in the people's such as Ah's Gaede (Argade) of issue on February 17th, 2009 U.S. Patent number 7,491, in on August 30th, 732 and 2007 disclosed U.S. Patent Application Publication No. 2007/0203161, both are combined in this by reference.

Synthesizing of compound

Compound I and II, together with salt III-VII as described below or by simulating following synthesizing.Those of ordinary skill in the art will understand alternative synthetic method.

Example 1

I:N2-(3-amino-sulfonyl-4-tolyl) the fluoro-N4-[4-of-5-(Propargyl oxygen base) phenyl]-2,4-thonzylamine

By 4-nitrophenol (1.00g, 7.19mmol), propargyl bromide (80wt% in toluene; 0.788mL, 7.09mmol) and K ₂cO ₃(1.08g, 7.84mmol) merges and stirring 18h at 60 ℃, in acetone (16.0mL).This reactant mixture is cooled to room temperature and water (200mL) dilution.By suction filtration, isolate 4-(Propargyl oxygen base) Nitrobenzol (1.12 _g), be white solid. ¹H?NMR(CDCl ₃):δ8.22(d,J=9.0Hz,2H),7.05(d,J=9.0Hz,2H),4.80(d,J=2.4Hz,2H),2.59(t,J=2.4Hz,1H)。

At 70 ℃, by 4-(Propargyl oxygen base) Nitrobenzol (0.910g, 5.13mmol), ferrum (1.42g, 25.3mmol) and NH ₄cl(0.719g, 12.8mmol) vigorous stirring 15 minutes in EtOH/ water (1:1,55mL).This reactant mixture is passed through to kieselguhr filtered while hot and concentrated in a vacuum.Residue is suspended in the 2N ammonia methanol of 10% in dichloromethane, sonication, and pass through diatomite filtration.The 4-that concentrate provides (Propargyl oxygen base) aniline, for a kind of oil, is used without being further purified. ¹H?NMR(CDCl3):δ6.82(d,J=8.7Hz,2H),6.64(d,J=8.7Hz,2H),4.61(d,J=2.4Hz,2H),2.50(t,J=2.4Hz,1H)。

At room temperature, by 4-(Propargyl oxygen base) aniline (0.750g, 5.10mmol) He 2, the chloro-5-fluorinated pyrimidine of 4-bis-(1.27g, 0.760mmol, commercially available from the Sigma Ao Ruiqi group (Sigma-Aldrich) of Wisconsin, USA Milwaukee) stirring 18h in MeOH/ water (4:1,35mL).By this reactant mixture EtOAc(200mL) dilute and use 1N HCl(50mL) and saline (50mL) wash.By the dry (MgSO of organic layer ₄), filter and concentrate in a vacuum.By this residue by column chromatography (silica gel, hexane gradual change is to EtOAc: hexane (1:10)) carry out purification, so that the fluoro-N4-[4-of the chloro-5-of 2-(the Propargyl oxygen base) phenyl that is light brown solid to be provided]-4-pyrimidinamine (0.514g). ¹h NMR (CDCl3): δ 8.03 (d, J=2.7Hz, 1H), 7.53 (d, J=8.7Hz, 2H), 7.02 (d, J=8.7Hz, 2H), 6.86 (s, 1H), 4.71 (d, J=2.4Hz, 2H), 2.55 (t, J=2.4Hz, 1H); LCMS: purity: 99%; MS (m/e): 279 (MH ⁺).

By the fluoro-N4-[4-of the chloro-5-of 2-(Propargyl oxygen base) phenyl]-4-pyrimidinamine (0.514g; 1.85mmol), 3-(amino-sulfonyl)-4-monomethylaniline. (0.689g; 3.70mmol; reduction manufacture or following description by commercially available 2-methyl-5-nitro benzenesulfonic acid amine are synthesized) and trifluoroacetic acid (0.186mL; 2.41mmol) and iPrOH(6.0mL) in a sealed vial, merge, and 100 ℃ heating 3h.This reactant mixture is cooled to room temperature and uses 1N HCl(80mL) dilution.By suction filtration, isolate N2-(3-amino-sulfonyl-4-tolyl) the fluoro-N4-[4-of-5-(Propargyl oxygen base) phenyl]-2,4-thonzylamine (I) (0.703g), is white solid. ¹h NMR (DMSO-d6): δ 10.08 (bs, 2H), 8.19 (d, J=4.5Hz, 1H); 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4Hz, 1H); 7.58 (d, J=8.7Hz, 2H), 7.32 (bs, 2H); 7.23 (d, J=8.4Hz, 1H), 6.97 (d, J=8.4Hz; 2H), 4.79 (d, J=2.1Hz, 2H); 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97%; MS (m/e): 428 (MH+).

The fluoro-N2-of II:5-(4-methyl-3-propionamido sulfonyl phenyl)-N4-[4-(Propargyl oxygen base) phenyl]-2,4-thonzylamine

By N2-(3-amino-sulfonyl-4-tolyl) the fluoro-N4-[4-of-5-(Propargyl oxygen base) phenyl]-2; 4-thonzylamine; I; (0.200g; 0.467mmol); DMAP(40mg, 0.33mmol) and triethylamine (0.118mL, 0.847mmol) at THF(6.0mL) in stir.In this solution, drip propionic andydride (0.180mL, 1.40mmol).This reactant mixture is at room temperature stirred and spent the night.By this for solution ethyl acetate (50mL) dilute and water (5x25mL) and saline (10mL) wash.By the dry (MgSO of organic layer ₄), filter and evaporation.Residue is suspended in ethyl acetate (25mL); sonication, and solid by filtration is collected to provide the fluoro-N2-of 5-(4-methyl-3-propionamido sulfonyl phenyl)-N4-[4-(Propargyl oxygen base) phenyl]-2,4-thonzylamine; II, (0.20g). ¹h NMR (DMSO-d ₆): δ 12.01 (s, 1H), 9.44 (s, 1H); 9.26 (s, 1H), 8.16 (d, J=2.4Hz; 1H), 8.06 (dd, J=0.3 and 3.3Hz, 1H); 8.00 (dd, J=2.1 and 7.8Hz, 1H), 7.69 (d; J=8.7Hz, 2H), 7.19 (d, J=8.4Hz; 1H), 6.95 (d, J=8.7Hz, 2H); 4.77 (d, J=2.1Hz, 2H), 3.56 (t; J=2.1Hz, 1H), 2.49 (s, 3H); 2.24 (q, J=7.2Hz, 2H); 0.89 (t, J=7.2Hz, 3H); LCMS: purity: 98%; MS (m/e): 484 (MH ⁺).

The fluoro-N2-of III: 5-(4-methyl-3-propionamido sulfonyl phenyl)-N4-[4-(Propargyl oxygen base) phenyl]-2,4-thonzylamine list sodium salt

By the fluoro-N2-of 5-(4-methyl-3-propionamido sulfonyl phenyl)-N4-[4-(Propargyl oxygen base) phenyl]-2; 4-thonzylamine, II, (0.125g; 0.258mmol) be suspended in acetonitrile (1.5mL) and water (1.5mL), and cooling in ice bath.Drip 1N NaOH aqueous solution (0.260mL).This reactant mixture is stirred until it becomes clarification, by glass cotton, filter, and lyophilizing is to provide the sodium salt of II. ¹h NMR (DMSO-d ₆): δ 9.17 (bs, 2H), 8.01 (d, J=3.6Hz; 1H), 7.89 (s, 1H), 7.78-7.69 (m; 3H), 6.99-6.92 (m, 3H), 4.76 (d; J=2.1Hz, 1H), 2.43 (s, 3H); 1.95 (q, J=7.2Hz, 2H); 0.86 (t, J=7.2Hz, 3H); LCMS: purity: 98%; MS (m/e): 484 (MH+).

Following compound is manufactured with a kind of and above those similar modes.

The fluoro-N2-[4-methyl-3-of IV:5-(N-propionamido sulfonyl) phenyl]-N4-[4-(2-propynyl oxygen base) phenyl]-2,4-thonzylamine potassium salt

¹h NMR (DMSO-d ₆): δ 9.16 (s, 1H), 9.14 (s, 1H), 8.01 (d; J=3.6Hz, 1H), 7.85 (d, J=2.1Hz, 1H); 7.75-7.70 (m, 3H), 6.97-6.92 (m, 3H), 4.76 (d; J=1.8Hz, 2H), 3.55 (t, J=2.4Hz, 1H); 2.42 (s, 3H), 1.91 (q, J=7.5Hz; 2H), 0.85 (t, J=7.5Hz, 3H); LCMS: purity: 97%; MS (m/z): 484 (female parent, MH ⁺).

The fluoro-N2-[4-methyl-3-of V:5-(N-propionamido sulfonyl) phenyl]-N4-[4-(2-propynyl oxygen base) phenyl]-2,4-thonzylamine calcium salt

¹h NMR (DMSO-d ₆): δ 9.16 (s, 2H), 8.00 (d, J=3.6Hz, 1H); 7.88 (d, J=1.8Hz, 1H), 7.75-7.69 (m, 3H); 6.97-6.92 (m, 3H), 4.76 (d, J=1.8Hz; 2H), 3.55 (t, J=2.1Hz, 1H); 2.43 (s, 3H), 1.94 (q, J=7.5Hz; 2H), 0.87 (t, J=7.5Hz, 3H); LCMS: purity: 98%; MS (m/z): 484 (female parent, MH ⁺).

The fluoro-N2-[4-methyl-3-of VI:5-(N-propionamido sulfonyl) phenyl]-N4-[4-(2-propynyl oxygen base) phenyl]-2,4-thonzylamine arginine salt

¹h NMR (DMSO-d ₆): δ 7.61 (d, J=3.9Hz, 1H), 7.57-7.55 (m; 1H), 7.36-7.31 (m, 1H), 7.12 (d; J=8.7Hz, 2H), 6.88 (d, J=8.7Hz; 1H), 6.72 (d, J=9.0Hz, 2H); 4.77-4.75 (m, 2H), 3.60 (t, J=6.0Hz; 1H), 3.09 (t, J=6.9Hz, 2H); 2.84-2.81 (m, 1H), 2.35 (s, 3H); 2.03 (q, J=5.7Hz, 2H), 1.80-1.72 (m; 2H), 1.61-1.48 (m, 2H); 0.855 (t, J=7.5Hz, 3H); LCMS: purity: 98%; MS (m/z): 484 (female parent, MH ⁺).

The fluoro-N2-[4-methyl-3-of VII:5-(N-propionamido sulfonyl) phenyl]-N4-[4-(2-propynyl oxygen base) phenyl]-2,4-thonzylamine choline salt

¹h NMR (DMSO-d ₆): δ 9.16 (s, 2H), 8.00 (d, J=3.6Hz, 1H); 7.85 (d, J=1.8Hz, 1H), 7.75-7.69 (m, 3H); 6.97-6.90 (m, 3H), 5.27 (t, J=4.8Hz, 1H); 4.76 (d, J=1.8Hz, 2H), 3.86-3.77 (m, 2H); 3.56-3.54 (m, 1H), 3.40-3.54 (m, 2H); 3.08 (s, 9H), 2.42 (s, 3H); LCMS: purity: 99%; MS (m/z): 484 (female parent, MH ⁺).

Example 2

5-amino-2-methyl benzsulfamide

4-Methylnitrobenzene (20mmol) is processed with chlorosulfonic acid (5.29mL, 80mmol) at 0 ℃, and then at this homogeneity solution, reached after room temperature, it is stirred 24 hours at 110 ℃.Then the slurry of generation is poured over to frozen water (100mg) upper, with ether (3x75mL), extracts, and organic facies water (75mL) is washed, then it is dried with anhydrous sodium sulfate.Then under reduced pressure except desolventizing is to provide thick sulfonic acid chloride, is absorbed into ethyl acetate and with ammonium hydroxide and at room temperature stir and spend the night.After separating ethyl acetate layer, water layer is extracted by ethyl acetate.Organic layer is merged, with anhydrous sodium sulfate, be dried, and under reduced pressure except desolventizing.By the oil obtaining by column chromatography (silica gel, hexane, be then in hexane 10%, 20% until 50% ethyl acetate) carry out purification, so that 3-amino-sulfonyl-4-Methylnitrobenzene, LCMS: purity: 95% to be provided; MS (m/e): 217 (MH+).

In the 3-amino-sulfonyl-4-Methylnitrobenzene solution in dichloromethane and methanol, add 10% Pd/C, and by this mixture under 50psi, under nitrogen atmosphere, shake 15 minutes.This mixture is filtered by kieselguhr and filter cake is washed with methanol.The organic solvent of merging is under reduced pressure concentrated to provide crude product, passed through flash column chromatography (ethyl acetate: hexane 1:1) carry out purification to provide 3-amino-sulfonyl-4-monomethylaniline., LCMS: purity: 87%; MS (m/e): 187 (MH+).

Example 3

The mensuration of this B cell line of Rameau stimulating with IL-4

A kind of means of measuring JAK inhibition are detection compound I and the effect of II to the rise of downstream gene product.Rameau this/during IL4 measures, with cytokine interleukin 4 (IL-4), stimulate B cell, cause the activation of the JAK/Stat path of the phosphorylation by JAK family kinase, JAK1 and JAK3 then phosphorylation and activating transcription factor Stat-6.One of gene that the Stat-6 being activated raises is low affinity IgE receptor, CD23.For example, in order to study inhibitor (, described herein 2, the pyrimidinediamine compounds that 4-replaces) to JAK1 and the kinase whose effect of JAK3, with this B cell of mankind IL-4 stimulating human Rameau.Stimulate latter 20 to 24 hours, cell is because the rise of CD23 is colored and uses flow cytometry art (FACS) to analyze.Compare with collating condition, the minimizing of the amount of the CD23 of existence shows that test compounds suppresses jak kinase path on one's own initiative.Exemplary being determined at below of this class is described in further detail.

The phosphorylation activation of the B cell stimulating with cytokine interleukin 4 (IL-4) by JAK family kinase JAK/Stat path, JAK1 and JAK3 then phosphorylation and activating transcription factor Stat-6.One of gene that the Stat-6 being activated raises is low affinity IgE receptor, CD23.In order to study the effect of inhibitor to JAK family kinase, with this B cell of mankind IL-4 stimulating human Rameau.

From ATCC(ATCC registration number CRL-1596) this B cell line of acquisition Rameau.According to ATCC breeding scheme, these cell culture are had to the RPMI1640(Cellgro ，Min Da scientific & technical corporation (MediaTech, Inc.) of 10% hyclone (FBS), He En on sale, Virginia, catalog number (Cat.No.) 10-040-CM) in, hot deactivation ((the JRH Biosciences of JRH biotechnology company, Inc.), Lai Neikesa, the Kansas State, catalog number (Cat.No.) 12106-500M).Cell is maintained to 3.5x10<sup TranNum="262">5</sup>density.Experiment the previous day, by this B cell dilution of Rameau to 3.5x10<sup TranNum="263">5</sup>cell/mL is to guarantee that they are in exponential phase.

Cell is rotated and be suspended in the RPMI with 5% serum.Each point in 96 hole tissue culture plate is used 5x10 ⁴individual cell.In the incubator of 37 ℃ by compound or DMSO(Sigma Ao Ruiqi group (Sigma-Aldrich) for cell, St. Louis, the Missouri State, catalog number (Cat.No.) D2650) preincubate 1 hour.Then cell is sent to Portec Inc. (Peprotech Inc.), Lip river Ji Shan, New Jersey, catalog number (Cat.No.) 200-04 with IL-4() stimulate the final concentration reach 50 units/mL for 20-24 hour.Then cell rotated and use anti-CD23-PE(BD Pharmingen company, Santiago, California, catalog number (Cat.No.) 555711) dye, and analyze by FACS.Use detects purchased from the BD LSR I system flow cytometer of the Bi Di Biological Science Co., Ltd (Becton Dickinson Biosciences) of San Jose.The IC that table 1 provides the result based on this mensuration to calculate ₅₀.

Example 4

The elementary mankind T-cell proliferating determining stimulating with IL-2

The JAK activity of these compounds described herein can be further by measuring Compound I described herein and the II sign that is used for to primary mankind T-cell proliferative response.In this measures, derived from the primary mankind T-cell of peripheral blood and the stimulation preactivate by T-cell receptors and CD28, in cultivation, respond cytokine interleukin II (IL-2) and breed.This breeder reaction depends on the activation of JAK1 and JAK3 tyrosine kinase, JAK1 and JAK3 tyrosine kinase phosphorylation and activating transcription factor Stat-5.Primary mankind T-cell is hatched 72 hours with Compound I and II under the existence of IL-2, and measuring terminal, measure the interior ATP concentration of cell with assessment cell viability.Compare with collating condition, the inhibition of jak kinase path has been indicated in the decline of cell proliferation.Exemplary being determined at below of this class is described in further detail.

Derived from the primary mankind T-cell of peripheral blood and the stimulation preactivate by T-cell receptors and CD28, responding in vitro cytokine interleukin II (IL-2) breeds.This breeder reaction depends on the activation of JAK-1 and JAK-3 tyrosine kinase, JAK1 and JAK3 tyrosine kinase phosphorylation and activating transcription factor Stat-5.

The primary T-cell of the mankind is prepared as follows.From a healthy volunteer, obtain whole blood, mix with PBS1:1, with 2:1 blood/PBS: ficoll ratio is in Ficoll-Hypaque (Ma Xiya biotech company (Amersham Pharmacia Biotech), Piscataway, New Jersey, catalog number (Cat.No.) 17-1440-03) higher slice, and at 4 ℃, at the centrifugal 30min of 1750rpm.To be positioned at serum: the lymphocyte of ficoll interface reclaims and by the PBS washed twice of 5 volumes.These cells are resuspended in to restructuring IL2(R and the d system that comprises 40U/mL, Minneapolis, the Minnesota State, catalog number (Cat.No.) 202-IL(20 μ g)) Yssel ' s culture medium (Gemini biological product, Wood is blue, California, catalog number (Cat.No.) 400-103) in, and inoculate the anti-CD3(BD Pharmingen company into precoating 1 μ g/mL, San Diego, California, catalog number (Cat.No.) 555336) and the anti-CD28(Immunotech company of 5 μ g/mL, the Beckman Ku Erte of mine-laying Asia, California, catalog number (Cat.No.) IM1376) in flask.Stimulate primary T-cell 3-4 days, then transfer them in a fresh flask and be held in the RPMI of the IL-2 with 10% FBS and 40U/mL.

By primary T-cell by PBS washed twice to remove IL-2, and with 2x10 ⁶cell/mL is resuspended in Yssel ' s culture medium.The cell suspending liquid of the IL-2 that 50 μ L are comprised to 80U/mL is added in each hole of flat 96 hole black dull and stereotyped (black plate).For unactivated contrast, IL-2 is saved from the last string of flat board.By compound at dimethyl sulfoxine (DMSO, 99.7% is pure, cell culture test, Sigma Ao Ruiqi group (Sigma-Aldrich), St. Louis, the Missouri State, catalog number (Cat.No.) D2650) in, from 5mM, with 3 times of dilute form, carry out serial dilution, and then in Yssel ' s culture medium, with 1:250, dilute.The 2X compound of 50 μ L is added in each hole in duplicate, and allows these cells at 37 ℃, to breed 72 hours.

Use CellTiter-Glo

fluorecyte determination of activity (CellTiter-Glo

luminescent Cell Viability Assay) (Pu Luomaige company (Promega)) measures propagation, and this measures the number based on living cells during quantitatively determining of the ATP existing cultivated, as the index of metabolic activity cell.Substrate is thawed and allow it to reach room temperature.By after Cell Titer-Glo reagent is together with mixing diluents, in each hole, add 100 μ L.These flat boards are mixed and with induction, are dissolved for two minutes on orbital shaker, and at room temperature hatch again ten minutes signal-balanced to allow.Use is purchased from Perkin Elmer company, Xie Erdun, and the Wallac Victor2 1420 multiaspect enumerators of the Connecticut State detect.The IC that table 1 provides the result based on this mensuration to calculate ₅₀.

Example 5

The A549 epithelial cell line stimulating with IFN γ

The JAK activity of these compounds described herein can also be by measuring Compound I described herein and the II sign that is used for to A549 pulmonary epithelial cells and U937 cell.A549 pulmonary epithelial cells and the multiple different stimulated of U937 cellular response and raise ICAM-1(CD54) surface expression.Therefore, use ICAM-1 to express as readout, can in same cell type, assess the effect of test compounds to unlike signal path.With IL-1 β, stimulate, by IL-1 beta receptor, activated TRAF6/NF κ B path, cause the rise of ICAM-1.IFN γ induces ICAM-1 to raise by the activation of JAK1/JAK2 path.The rise of ICAM-1 can be carried out quantitatively across compound agent discharge curve by flow cytometry, and calculates EC ₅₀value.Exemplary being determined at below and in example 6 of this class is described in further detail.

A549 pulmonary epithelial cells responds multiple different stimulated and raises ICAM-1(CD54) surface expression.Therefore, use ICAM-1 to express as readout, can in same cell type, assess the effect of compound to unlike signal path.IFN γ raises ICAM-1 by the activation of JAK/Stat path.In this example, the rise of assessment IFN γ to ICAM-1.

A549 lung epithelial cancerous cell line is derived from U.S.'s germplasm and preserves center.Cellar culture is F12K culture medium (the Min Da scientific & technical corporation (Mediatech Inc.) that uses hyclone, the penicillin of 100I.U. and the streptomycin of 100ng/mL with 10%, Lai Neikesa, the Kansas State, catalog number (Cat.No.) 10-025-CV) (F12k culture medium completely).CO by cell at 37 ℃, 5%<sub TranNum="284">2</sub>humid atmosphere in hatch.Before using in this is measured, by A549 cell with PBS washing and by trypsin treatment (Min Da scientific & technical corporation (Mediatech Inc.), catalog number (Cat.No.) 25-052-CI) to float these cells.With in complete F12K culture medium and trypsin cell suspending liquid and centrifugal to precipitate these cells.Cell precipitation is pressed to 2.0x10<sup TranNum="285">5</sup>/ mL concentration is resuspended in complete F12K culture medium.Cell is inoculated in flat tissue culture plate, 20,000, each hole, 100 μ L cumulative volumes, and allow its adhesion to spend the night.

At second day, the thonzylamine test compounds that A549 cell is replaced with 2,4-or DMSO(contrast) (Sigma Ao Ruiqi group (Sigma-Aldrich), St. Louis, the Missouri State, catalog number (Cat.No.) D2650) preincubate 1 hour.Then use IFN γ (75ng/mL) (sending Portec Inc. (Peprotech Inc.), Lip river Ji Shan, New Jersey, catalog number (Cat.No.) 300-02) to stimulate these cells, and allow it to hatch 24 hours.Final test compounds dosage range is 30 μ M to 14nM in the F12K culture medium that comprises 5% FBS, 0.3% DMSO of 200 μ L.

At the 3rd day, remove cell culture medium, and with 200 μ L PBS(phosphate buffered saline (PBS)s) wash these cells.Trypsin treatment is used to so that then these cell separation neutralize by adding the complete F12k culture medium of 200 μ L in each hole.By cell precipitation, and at 4 ℃, with the mice Anti-Human class ICAM-1(CD54 of APC conjugation) (BD Pharmingen company, San Diego, California, catalog number (Cat.No.) 559771) antibody staining 20 minutes.Cell is washed with ice-cold FACS buffer agent (PBS+2%FBS), and express by flow cytometry surface ICAM-1.Use detects purchased from the BD LSR I system flow cytometer of the Bi Di Biological Science Co., Ltd (BD Biosciences) of San Jose.Effective scattering of gate event (live scatter), and calculate geometric mean (Bake pause Angie Dickinson CellQuest software version 3.3, Hu， New Jersey, Franklin).Geometric mean is marked and drawed to produce a dose-effect curve for compound concentration.The IC that table 1 provides the result based on this mensuration to calculate ₅₀.

Example 6

U937IFN γ ICAM1FACS measures

U937 human monocyte responds multiple different stimulated and raises ICAM-1(CD54) surface expression.Therefore, use ICAM-1 to express as readout, can in same cell type, assess the effect of compound to unlike signal path.IFN γ raises ICAM-1 by the activation of JAK/Stat path.In this example, the rise of assessment IFN γ to ICAM-1.

From Maryland State Rockville's ATCC, obtain U937 human monocyte system, catalog number (Cat.No.) CRL-1593.2, and it is being comprised to 10%(v/v) the RPM1-1640 culture medium of FCS in cultivate.U937 cell is grown in 10% RPMI.Then these cells are put into the 96 flat flat boards in hole with the concentration of 100,000 cell/160 μ L.Then test compounds is diluted as follows: the test compounds 1:5 of 10mM is diluted in to 3 μ L, 10mM test compounds in the DMSO of DMSO(12 μ L) in, follow by the 1:3 serial dilution of test compounds in DMSO (the test compounds serial dilution of 6 μ L being entered in the DMSO of 12 μ L to provide 3 times of dilutions).Then the test compounds of 4 μ L is transferred to 10% the RPMI of 76 μ L, generates 10X solution (test compounds of 100 μ M, 5% DMSO).For control wells, the DMSO of 4 μ L is diluted in the 10%RPMI of 76 μ L.

With 8 points (from 83 times of diluted concentrations of 10 μ l), carry out this in duplicate and measure, and under the condition of 4 holes (control wells) of wherein only having DMSO in stimulating, and under the condition of 4 holes only having DMSO in not stimulating.

Use the Beckman Ku Erte of multimek(mine-laying Asia, California) the dull and stereotyped 2X of diluted compounds is mixed, and then the diluted compounds of 20 μ L is transferred in 96 hole flat boards of the cell that comprises 160 μ L, then by flat board twice of mixed on low speed again.Then under 37C, the CO with 5% ₂by cell and compound preincubate 30 minutes.

By preparing mankind IFN γ 100ng/mL solution in 10% RPMI, manufacture 10X and stimulate mixture.Then with the IFN γ of 20 μ L, stimulate mixture to stimulate in these cells and compound, to provide the IFN γ of 10ng/mL, the final concentration of the DMSO of the test compounds of 10 μ M and 0.5%.By these cells under 37C, the CO with 5% ₂, under the condition for stimulating, keep 18-24 hour.

These cells are transferred to 96 hole circle base plates for dyeing, and then remain on ice for staining procedure is continued.By cell at 4 ℃, 1000rpm rotation 5 minutes, remove subsequently supernatant.After removing supernatant, to the mice Anti-Human class ICAM-1 antibody that adds the APC conjugation of 1 μ L in every 100 μ L FACS buffer agents.Then by cell on ice, hatch 30 minutes in the dark.After hatching, add the FACS buffer agent of 150 μ L, and by these cells at 4 ℃, under 1000rpm centrifugal 5 minutes, remove subsequently supernatant.After removing supernatant, add the FACS buffer agent of 200 μ L, and these cells are resuspended.After suspension, by these cells at 4 ℃, under 1000rpm centrifugal 5min.Then, before in the FACS buffer agent that these cells is resuspended in to 150 μ L, remove supernatant.

Use detects purchased from the BD LSR I system flow cytometer of the Bi Di Biological Science Co., Ltd (BD Biosciences) of San Jose.Effective scattering of gate living cells, and measure the geometric mean (Bake pause Angie Dickinson CellQuest software version 3.3, Hu， New Jersey, Franklin) of CAM-APC.Analyze % living cells and ICAM-1 and express both.For the mensuration of test compounds and the control compound of known activity is parallel carries out.The EC of control compound ₅₀40-100nM typically.The IC that table 1 provides the result based on this mensuration to calculate ₅₀.

Example 7

Medicament preparation

This example has been described the medicament preparation (understanding is also comprised to its salt) of inclusion compound I or II.This type of preparation is to prepare as known to persons of ordinary skill in the art, and extra preparation is being considered this example and after this extra disclosure, to those of ordinary skill in the art, is being easily apparent.

Table 2

Every kind of preparation 1 – 7 above uses in three dose concentrations: 0.001%, 0.003% and 0.01%(w/w) Compound I or II prepare.Every kind of preparation is all by add the tonicity agent (mannitol) of specified amount in a flask, is heated to approximately 50 ℃ and prepares in the about appointment buffer agent of the final volume of half (phosphate or citrate).After heating, the Compound I of interpolation appropriate amount or II are together with extra as indicated excipient (glycerol and/or PEG400).Add purifying waste water of q.s.This mixture is stirred to homogeneity (approximately five minutes), and then the filter membrane by sterilizing is filtered in sterile chamber by it.If necessary, by adding the NaOH of 1.0N, regulate pH.

Optionally, for example have the Compound I of higher concentration or II(, preparation 0.03%w/w) can comprise a kind of surfactant and a kind of stabilization of polymer optionally.With reference to preparation 6 and 7, preferred surfactant comprises Triton X114 and tyloxapol, they are respectively from Sigma Ao Ruiqi group (Sigma-Aldrich) (St. Louis, the Missouri State) and piezochemistry company (Pressure Chemical Company) (Pittsburgh, Pennsylvania) be commercially available.Preferred stabilization of polymer comprises carbomer carbopol 974p(carbomer Carbopol974p) (commercially available from Lubrizol Corp. (Lubrizol), Wyclif, Ohio).

First preparation 6 and 7 by being scattered in carbomer in surfactant and preparing, the buffer agent of its final concentration that this surfactant comprises 10X (for example, pH6.5,3% tyloxapol in the phosphate buffer of 50mM, has 2.5% mannitol and 5% Carbomer974 p(Carbomer974p)).Then also with its final concentration of 10X by Compound I also or Compound I I be scattered in this preconcentrate.Make this mixture homogeneous, wherein by the 10x dilution at a kind of preconcentrate filtering in coordinating buffer agent, obtain final preparation.

Preparation and test are described in for example Lei Mingdun for the method for the medicine of local application, The Science and Practice of Pharmacy(" pharmaceutical science and put into practice ") (the 21st edition), in 872-882 page (2006).This medicine is prepared for a desirable degree of depth to skin surface by drug delivery, avoided the unwanted systemic Absorption of this medicine simultaneously.Can in said composition, add different penetration enhancers, for example alcohol, alkyl-dimethyl sulfoxide, ketopyrrolidine, laurocapram, dimethyl formamide, tetrahydrofurfuryl alcohol, amphiphile or other diversified reinforcing agents (for example clofibric acid amide, heyamethylene lauric amide, proteolytic enzyme, terpenes or sesquiterpene).These penetration enhancers have improved the drug delivery that enters skin.

In a particular instance of this preparation, used the ethanol of the 60:20:20 with enough propylene glycol: propylene glycol: aqueous systems maintains the reactive compound of 0.5%-2%.

The common composition that can be used for giving this compound with local preparation form is carrier, for example hydrophobicity carrier, for example Hydrocarbon, liquid vaseline (mineral oil, liquid paraffin, paraffin oil), white petrolatum (petroleum jelly, VASELINE), yellow petrolatum (vaseline), squalane (perhydro zamene, ten dihydro Squalenes (spinacane)) and silicone; Silicone, for example liquid polydimethylsiloxane (simethicone, silicone rubber, medical grade silicone oil); Alcohol, for example dodecyl alcohol (1-dodecyl alcohol, dodecyl alcohol)), myristyl alcohol (tetradecanol, tetradecyl alcohol), cetyl alcohol (hexadecanol, ethal, palmityl alcohol), stearyl alcohol (stenol, cetosteryl alcohol), oleyl alcohol (ocenol); Sterin, for example sterin fat; Lanoline, for example agnolin (hydrous wool fat, lanum); Anhydrous lanolin (for example lanoline, anhydrous lanolin (anhydrous lanum), agnin (agnin)); Semi-synthetic lanoline; Carboxylic acid, for example lauric acid, myristic acid, Palmic acid, stearic acid, oleic acid; Fat and polyester, for example cholesterol ester (stearate), ethylene glycol monoester, propylene glycol monoester, glycerol monoester, glyceryl monostearate, sorbitol monoester, anhydro sorbitol monoester, sorbitol two fat, anhydro sorbitol polyester (this dish (span), I rope (arlacel)), glycerol tristearate, Adeps Sus domestica, almond oil, Semen Maydis oil, Oleum Ricini, Oleum Gossypii semen, olive oil, soybean oil, hydrogenated oil and fat, sulfated oil, isopropyl myristic acid fat, isopropyl palmitic acid lipid; Ether and polyethers, for example polyethylene-polypropylene ethylene glycol (pluronic (pluronic)).

Can comprise polyhydric alcohol and Polyethylene Glycol by intersolubility carrier as the water of cosolvent, for example propylene glycol (1,2-propylene glycol), glycerol (glycerol), liquid polyethylene glycol, solid polyethylene glycol (hard macrogol, carbowax), 1,2-phenol-hexanetriol, sorbitol solution; Ester and polyester, for example polyethenoxy sorbitan monoester (stearate-tween) and polyethenoxy sorbitan polyester (tween); Ether and polyethers, for example polyethyleneglycol cetyl ether (polyethylene glycol monocetyl ether) (polyethyleneglycol cetyl ether 1000) and polyethylene-polypropylene ethylene glycol (pluronic (pluronic).

Can in said composition, add different structural matrix formations, for example Hydrocarbon, for example white petrolatum (petroleum jelly, VASELINE), yellow petrolatum (petroleum jelly), paraffin (hard paraffin (paraffin wax, hard paraffin)), microwax, ceresine (mineral tallow, purification ceresine); Silicone, for example gas-phase silica (fumed silica) (cab-O-sil), bentonite (colloidal alumina silicate) and aluminium-magnesium silicate (colloidal magnesium aluminosilicate); Polyhydric alcohol and polyvalent alcohol, for example solid polyethylene glycol (hard macrogol, carbowax); Alcohol, for example cetyl alcohol (hexadecanol, ethal, palmityl alcohol), stearyl alcohol (stenol, cetostearyl alcohol (cetosteryl alcohol)); Sterin and sterin fat, for example cholesterol (cholesterin), lanoline, anhydrous lanolin and semi-synthetic lanoline; Carboxylic acid, for example lauric acid, myristic acid, Palmic acid, stearic acid, oleic acid; And fat or polyester, for example Cera Flava, cera alba (bleached bees wax), Brazil wax, myricin, cholesterol ester (stearate), polyoxyethylene sorbitan, Adeps Sus domestica or hydrogenated oil and fat.

These compositionss may further include suspending agent, gellant or viscosity derivant, for example silicone, for example gas-phase silica (cab-O-sil), bentonite (colloidal alumina silicate) or aluminium-magnesium silicate (colloidal magnesium aluminosilicate); Polycarboxylate, poly-sulfuric ester or polysaccharide (for example agar), alginate, carragen, arabic gum, Tragacanth, methylcellulose, carboxymethyl cellulose, hydroxyethyl-cellulose, carboxy vinyl polymer, gelatin, pectin, xanthan gum, polyacrylic acid.

Some embodiment can comprise a kind of water in oil emulsion, for example sterin or sterol ester, for example cholesterol (cholesterin), lanoline (agnolin (hydrous wool fat, lanum)), anhydrous lanolin (lanoline, anhydrous lanolin (anhydrous lanum), agnin (agnin)) or semi-synthetic lanoline; Carboxylic acid, for example Na+ of lauric acid, myristic acid, Palmic acid, stearic acid, oleic acid, K+, ethanolamine salt; Or ether or polyethers, for example polyethylene-polypropylene ethylene glycol (pluronic (pluronic)).If wish a kind of oil-in-water (o/w) Emulsion, example is ester and polyester, for example polyethenoxy sorbitan monoester (stearate-tween), polyoxyethylene fat (stearic acid-Polyethylene Glycol monoesters, Myrj), polyethenoxy sorbitan polyester (tween); Ether and polyester, for example polyethyleneglycol cetyl ether (polyethylene glycol monocetyl ether) (polyethyleneglycol cetyl ether 1000) or polyethylene-polypropylene ethylene glycol (pluronic (pluronic)); And other, for example sodium lauryl sulfate, Borax (sodium borate), ethanolamine or triethanolamine.

For the applicable surfactant using at these preparations, comprise, but be not limited to: non-ionic surface active agent, image surface activating agent 190(dimethicone copolyol (dimethicone copolyol)), polysorbate 20 (polysorbas20), polysorbate 40 (polysorbate40), polysorbate 60 (polysorbate60), polyoxyethylene sorbitan monoleate (Tween 80), lauric amide DEA, coconut oleoyl amine DEA, with coconut oleoyl amine MEA, amphoteric surfactant, picture oleyl betanin and cocamido propyl betaine (Velvetex BK-35), and cationic surfactant, picture PHOSPOLIPID PTC cocamidopropyl phosphaidyl PG-dimonium chloride (coconut oleoyl amine phosphatidyl pg dimonium chloride).Can also use suitable combination or the mixture of this type of surfactant.

For the applicable wetting agent using at preparation of the present invention, include, but are not limited to: lactic acid and other hydroxy acid and salt, glycerol, propylene glycol, butanediol, sodium PCA, carbowax 200, carbowax 400 and carbowax 800.For the applicable softening agent using at preparation of the present invention, comprise, but be not limited to: PPG-15 stearyl ether, lanonol, lanoline, lanolin derivative, cholesterol, vaseline, iso stearyl pivalate, octyl group stearate, mineral oil, iso-spermaceti ester alcohol stearic acid, Ceraphyl424(nutmeg base myristate), octyldodecanol, dimethyl silscone (DOW CORNING 200-100cps), phenyl trimethyl silicone (DOW CORNING 556), DOW CORNING 1401(Cyclomethicone and dimethiconol), and Cyclomethicone (DOW CORNING 344), and Miglyol840(is manufactured by Huls, propylene glycol dicaprylate/dicaprate).In addition, according to the present invention, can use the appropriately combined and mixture of any these wetting agents and softening agent.

Said composition can also comprise antiseptic and antimicrobial, for example benzalkonium chloride, benzoic acid, benzyl alcohol, bronopol, chlorhexidine, chlorocresol, imidazolidinyl urea, Nipagin ester, phenol, phenoxyethanol, potassium sorbate or sorbic acid; Antioxidant, for example alpha-tocopherol, ascorbic acid, ascorbyl palmitate, Butylated hydroxyanisole, sodium ascorbate, sodium pyrosulfite; Chelating, for example citric acid or edetic acid; Buffer agent, for example citric acid and salt, phosphoric acid and salt, H ₃pO ₄/ NaH ₂pO ₄, glycine, acetic acid, triethanolamine or boric acid; Wetting agent, for example glycerol (glycerol), propylene glycol (E1520), glyceryl triacetate (E1518), sorbitol (E420), xylitol and maltose alcohol (E965), polydextrose (E1200), soapbark (E999), lactic acid, urea or lithium chloride; And/or chelating antioxidant, for example citric acid and salt thereof, ethylenediaminetetraacetic acid (Versene, EDTA).

A specific embodiment of topical therapeutic is a kind of ointment, and this ointment is a kind of for the semi-solid preparation to skin or mucosa external application.In a particular instance, this ointment is based on vaseline.This ointment does not comprise for it at room temperature being isolated to the enough water of a second-phase.Can prepare with Polyethylene Glycol the ointment of water soluble.Ointment is desirable softening agent, the adhesiveness that the percutaneous permeability having had and effects on surface are good.This ointment is in one easily in container, for example pipe or wide mouthed bottle.

Alternately, this topical formulations is a kind of emulsifiable paste, and wherein these compounds are dissolved or be suspended in removable water or in softening agent substrate.These emulsifiable pastes can be Water-In-Oil also or oil-in-water compositions.Immiscible compound can merge by mechanical agitation or the heating of the method with moist colloid, dryness colloid, bottle and beaker.In certain embodiments, this emulsifiable paste is a kind of oil in water emulsion or has long-chain fatty acid or the aqueous crystallite dispersion of alcohol, and these long-chain fatty acid or alcohol are that water can wash away and are that beauty treatment is upper and aesthetic more acceptable.

In other embodiments, provide these active component to be used to give with a kind of form of paste, can think that paste is a kind of ointment that has wherein added the insoluble solids of high percent (for example, by weight up to 50%).Due to the existence of solid, this paste is than hard many of ointment, and these solids form a kind of matrix of microparticles in the ointment structure having existed.Composition, for example starch, zinc oxide, calcium carbonate and Talcum, can be used as solid phase.Paste provides particularly preferred protective barrier on skin.Similar ointment, paste forms complete, a relatively fluid-tight film at skin surface; Unlike ointment, this tunic is opaque and is therefore a kind of effective sunlight filtrate.Therefore, it is effective especially that paste is avoided ultraviolet radiation for protection skin, and ultraviolet radiation can worsen the disease (for example DLE) for the treatment of.

Still, in other other embodiment, this activating agent is provided with the form of gel, jelly or lotion.Gel is to cause in the jellied waterborne liquid carrier of change by adding gellant, the semisolid systems being comprised of micromolecule or macromolecular dispersion.In gellant, use be synthetic macromolecule (for example carbomer 934) and cellulose derivative (for example carboxymethyl cellulose or hydroxypropyl methylcellulose).Gel and many materials are compatible, and can comprise penetration enhancers and enter sending of skin to improve.These gels can be single-phase gels, and wherein these macromole are scattered in whole liquid equably, at the macromole disperseing, there is no obvious border between this liquid; Or can be two-phase gel, wherein this gel group be comprised of the floccule with little different granule, is commonly called paste.The substrate that jelly comprises water soluble, this matrix composition is from natural gum, for example Tragacanth, pectin, alginate or boric acid glycerin; Or preparation is from natural materials, the synthesis of derivatives of methylcellulose or carboxymethyl cellulose for example.Lotion is the settled solution of the alcohol of a kind of 25%-50% of comprising, and it optionally comprises a kind of antiseptic or softening agent.Extract, menthol, glycerol, boric acid, Alumen or the oxyquinoline potassium that can be Radix Hamamelidis Molliss to other optional compositions that add in this lotion.

In another embodiment, this compound is used with the form of powder, this powder packets is containing very meticulous granular size, and these granular sizes produce surface area that per unit weights are large to cover the surface area that health is larger and to provide lightweight to disperse.Alternately, this compound is used with the form of solution, it is the liquid preparation that is dissolved in for example, solvable chemicals in solvent (water, alcohol or propylene glycol).Still, in other examples, it is a kind of Emulsion of biphase preparation, and wherein a phase (decentralized photo or interior phase) is scattered in another phase (continuous phase or foreign minister) well.This decentralized photo also can have hydrophobic group (oil-in-water) or aqueous base (Water-In-Oil).Because there are two kinds of incompatible phases of combining closely, so this Emulsion will typically comprise a kind of physically stable system, for example surfactant (ion or non-ionic), polymer (non-ionic polyalcohol, polyelectrolye or biopolymer) or its mixture.

For the embodiment of this compound is wherein provided with form of suspension, this dosage form comprises biphase.Continuous phase or foreign minister be liquid or semisolid normally, and decentralized photo or interiorly formed by particle matter, this particle matter is insoluble to continuous phase in essence, but is scattered in whole continuous phase.This insoluble matter can for example be used for physiological role by external coating.Although this suspension system is can be when standing separated, the speed of sedimentation can reduce by changing this preparation, is used for after shaking its container, at the dosage at least needing, keeps the compositions of enough homogeneity in the necessary period.

This compound can also be given the form with aerosol, this depends on the strength of content being discharged to gas compression or liquefaction of this container.Propellant in this container is responsible for developing suitable pressure in this container, and when this valve open, it is discharged product and helps the atomization of these products or foam to produce.Topical remedy's aerosol utilizes the gas (for example nitrogen, carbon dioxide and nitrous oxide) of Hydrocarbon (propane, butane and isobutene .) and compression.

Any these dosage forms can inclusion compound I/II and the deposit separating of a kind of auxiliary agent (for example for activated compounds II to form the reagent of Compound I).

Example 9

Cutaneous lupus mouse model

This example has been described the purposes that mouse model is used for screening the treatment of cutaneous lupus (for example DLE), comprises the selection of the scheme for the treatment of, prevention and therapeutic alliance.The compound that carrys out test request with animal model for example, together with formulated in combination product (described here those).In instantiation, the local preparation of inclusion compound I and/or II is applied to the skin of this animal and therapeutic response is assessed.These preparations are being given to this animal, for the quantity reducing of skin injury or the sign of seriousness, skin is being checked.

Although not yet find the single model based on animal of analog D LE ideally, MRL/lpr mouse species has been useful as research tool.By the genetically modified of these autoimmune mices or gene knockout form, probed into the performance of cutaneous lupus.In MRL/lpr mice, lpr sudden change causes the exchange of Fes gene, and apoptotic defect causes having the abnormal lymphopoiesis of abnormal function and the generation of autoantibody.These animals are developed into spontaneous lupoid acne skin injury, and these skin injurys are early stage common and along with Mouse Age becomes more and more serious at life.High Switzerland (Ghoreishi) and Da Tezi (Dutz), Lupus(" lupus ") 19:1029-1035 (2010).

Mouse model is TCR α-/-mice of processing by fluorouracil and ultraviolet B rayed, to induce cutaneous lupus damage.Gu Chuan (Furukawa) and Yoshimasu, the comment of Autoimmunity Reviews(autoimmune) 4:345-350 (2005).

Yet, for the preferred mouse model proving and test now disclosed therapeutic effect, be at present to use (NZBxNZW) F1 mice that easily sends out lupus, as Guiducci(Kui Duqi) etc. people, Journal of Experimental Medicine(" The Journal of Experimental Medicine ") disclosed in 207:2931-2942 (2010), by it by reference and combination.In band shape, peel off (tape stripping) afterwards, these mices that easily send out lupus develop the chronic skin injury that is similar to the chronic lupus erythematosus of the mankind.

(NZBxNZW) F1 mice that easily sends out lupus is obtainable from Jackson Lab (The Jackson Laboratory), and can during age in week, use at 18-22.C57BL/6 in contrast and 129 mices are obtainable (for example, from Charles River companies).The dorsal area of these mices is shaved out to the area of a 3x3cm, and with cloth base adhesive tape, carried out band shape and peel off (tape stripping) 10 times.This skin will illustrate increase in the quantity PDC and neutrophil(e) cell, and what follow abundant Premeabilisation of cells thing is the expression of the increase of IFN-regulator gene and proinflammatory gene.Band shape is peeled off (tape stripping) approximately three weeks afterwards, and these mices have the hole (crater) following Hyperkeratotic outstanding epidermal hyperplasia, be full of cutin or the degeneration of cyst, corium fabric and subcutaneous fat.These variations are similar to those that see in suffering from the mankind of chronic lupus erythematosus.

In this model, use the different approach that gives, dosage and scheme that this mice is exposed to test agent.In instantiation, will be applied to partly the region of having been peeled off or will have been peeled off by band shape by band shape at these these disclosed medicines.Alternately, by this testing drug general give.Before or after band shape is peeled off, by this medicine, with the interval of fixing, give one or many (for example, band shape is peeled off afterwards or appear every day afterwards in skin injury).Can be by measuring such labelling of disease, as the number of skin injury, surface area or outward appearance are assessed drug reaction.Even if the number of damage or surface area do not reduce, but assessment is in the reaction of test treatment, can measure the seriousness (for example level of erythema) of damage.Also carried out the histologic analysis of dermatological specimens, and be divided into 1 to 3 grade based on following index: (a) epidermal thickness; (b) ulcer level; (c) upper Intradermal inflammation; (d) corium inflammation; And (e) film inflammation.Histological grade is specified as follows: 0: normal skin structure, seldom corium leukocyte, and regular adnexa; 1: light inflammation, a small amount of epidermal hyperplasia, and the sign of dermal fibroblast hypertrophy; 2: moderate inflammation, follow Hyperkeratotic obvious epidermal hyperplasia (epithelial thickness increases by two to four times), there is seldom significant leukocyte/neutrophil cell corium penetrant of macrophage, the moderate fibrosis of corium, the minimizing of adnexa number, and the slight degeneration of subcutaneus adipose tissue; And 3: serious inflammation, follow Hyperkeratotic significant epidermal hyperplasia (epithelial thickness increases over four times), be full of the hole (crater) of cutin or the formation of cyst, the diffusivity of epidermal area is interrupted (diffuse discontinuity) (ulcer), there is a large amount of corium penetrant that enriches neutrophil(e) cell and macrophage, obvious corium fabric, the disappearance of adnexa, and the obvious degeneration of subcutaneus adipose tissue.These different parameters are given a mark and sued for peace to obtain a total disease mark.Can process Premeabilisation of cells thing with flow cytometry.

Example 10

Therapeutic Method and formulated in combination product

The experimenter that for example, clinical manifestation based on lupus erythematosus,cutaneous (DLE, ACLE, SCLE or DILE) selects the preparation of stand-by requirement to treat.This example has been discussed the treatment of DLE definitely, but similar Therapeutic Method can be used for to other skin forms of lupus, for example ACLE, SCLE or DILE.Although the compositions requiring can also be used or general gives more at large to skin, their are the DLE of application to skin damage partly conventionally, for example the only DLE of application to skin damage.Treatment can continue at least one week, one month or 1 year, and in some experimenters, treatment may extend to for many years, the persistent period of disease or this experimenter all one's life.

In concrete situation, select and experimenter other drug or that non-pharmaceutical intervention (for example general PLAQUENIL or topical corticosteroid) is treated together.In other cases, Compound I and/or II for example, are not given with together with other treatment (general PLAQUENIL or general or topical corticosteroid) for LE or DLE.In other embodiments, the method comprises this treatment given to an experimenter who suffers from DLE, and this experimenter does not have Anti-DNA antibody, for example anti-dsDNA antibody.

For example, for example, by lupus erythematosus,cutaneous (chronic skin lupus erythematosus, DLE) being made to diagnosis, select experimenter.In this instantiation, select not suffer from the experimenter of SLE (for example,, by not thering is anti-dsDNA antibody, or the performance of the general of SLE, for example, except the skin or mucosa of eyes, nose or mouth, the inflammation of kidney, lung, central nervous system or any organ).In other examples, this experimenter only has the cutaneous manifestations of disease at body surface, and does not have damage at any other organ of health.Form by the compound of a treatment effective dose with a kind of local petroleum jelly preparation provides, and this preparation is applied directly to lupus erythematosus,cutaneous damage, for example, to the squamous papule on the extensor surface of trunk and extremity and/or scalp.This medicament preparation is applied to these damages every day, and for example every day 2-4 time, lasting more than one day, for example at least one week.Continuation is to these damage local application this preparations, until the damage of using this preparation to it disappears or disappears, or its progress delay or stop.

In other examples, this treatment compound is pressed to effective dose, with the form of sunscreen preparation, provide; and be exposed to before ultraviolet radiation; apply it to skin, to protect, avoid being exposed to ultraviolet radiation, ultraviolet radiation is the trigger of cutaneous lupus damage outburst normally.This sunscreen preparation can comprise for example PABA or the zinc oxide of an effective dose minimizes the skin that is exposed to ultraviolet radiation.

The therapeutic alliance that the compound with Formula I and/or II (comprising its salt) for example, is merged with the medicament of another kind for the treatment of cutaneous lupus or another disease (disease being associated with xerophthalmia) is also provided.The formulated in combination product that are used for the treatment of cutaneous lupus (for example DLE) comprise following formulated in combination product, and these formulated in combination product comprise a kind of topical corticosteroid (for example organizing I, II, III, IV, V, VI or VII corticosteroid), for example any following:

Group I(is effective force very: compares with hydrocortisone, stronger up to 600 times)

Clobetasol propionate 0.05%(dermovate (Dermovate))

Betamethasone dipropionate 0.25%(betamethasone (Diprolene))

Halobetasol propionate ester 0.05%(Ultravate)

Oxalic acid diflorasone ester 0.05%(Suo Kang frost (Psorcon))

Group II

Acetic acid fluocinolone acetonide 0.05%(fluocinolone acetonide (Lidex))

Halcinonide 0.05%(halcinonide (Halog))

Amcinonide 0.05%(Cyclocort)

Desoximetasone 0.25%(desoximetasone (Topicort))

Group III

Triamcinolone acetonide 0.5%(triamcinolone acetonide (Kenalog), Kenac Cream (Aristocort cream))

Momestasone furoate 0.1%(mometasone (Elocon) ointment)

Fluticasone propionate 0.005%(Cutivate (Cutivate))

Betamethasone dipropionate 0.05%(betamethasone dipropionate (Diprosone))

Group IV

Fluocinolone acetonide 0.01%-0.2%(fluocinonide (Synalar, Synemol, Fluonid))

Valeric acid hydrocortisone 0.2%(Westcort)

Hydrocortisone butyrate 0.1%(Locoid)

Flurandrenolide 0.05%(Cordran)

Triamcinolone acetonide 0.1%(triamcinolone acetonide (Kenalog), triamcinolone acetonide A ointment (Aristocort A ointment))

Momestasone furoate 0.1%(mometasone (Elocon) emulsifiable paste, lotion)

Group V

Triamcinolone acetonide 0.1%(triamcinolone acetonide (Kenalog), Kenac Cream, lotion (Aristocort cream, lotion))

Fluticasone propionate 0.05%(Cutivate (Cutivate) emulsifiable paste)

Desonide 0.05%(Tridesilon, DesOwen ointment)

Fluocinolone acetonide 0.025%(fluocinolone acetonide cream (Synalar, Synemol cream))

Valeric acid hydrocortisone 0.2%(Westcort emulsifiable paste)

Group VI

Prednicarbate 0.05%(Aclovate emulsifiable paste, ointment)

Triamcinolone acetonide 0.025%(triamcinolone acetonide A emulsifiable paste (Aristocort A cream), triamcinolone acetonide lotion (Kenalog lotion))

Fluocinolone acetonide 0.01%(Capex shampoo, Dermasmooth)

Desonide 0.05%(DesOwen emulsifiable paste, lotion)

Group VII

Hydrocortisone 2.5%(hydrocortisone (Hytone) emulsifiable paste, lotion, ointment)

The many brands that do not need prescription to sell of hydrocortisone 1%()

In some instances, experimenter is diagnosed as also suffers from a kind of imbalance except cutaneous lupus, and wherein this extra imbalance is not caused by lupus erythematosus, or is not performance lupus erythematosus or associated with it.For example, the experimenter with the damage of cutaneous lupus eyelid also may be diagnosed as xerophthalmia, and gives therapeutic alliance to this experimenter.In an example, find that experimenter has and will the local application of corticosteroid (for example prednisone acetate dragon ophthalmic suspension 1%) be had to the meibomitis of response.The compound (comprising its salt) with Formula I and/or II is suspended in prednisolone preparation and by one sky and instils or be applied to eyes 2 to 4 times.In other examples, if xerophthalmia is associated with seasonal irritated other inflammatory disease of crossing, can or it be given with preparation form collyrium preparation a kind of with it so, this preparation comprises antihistaminic (pheniramine for example, emedastine, or azelastine), decongestant drug (for example tetrahydrozoline hydrochloride or naphazoline), or non-steroidal anti-inflammatory agent (for example nepafenac or ketorolac), corticosteroid (for example fluorometholone or loteprednol), mast cell stabilizers (azelastine for example, cromal, emedastine, ketotifen, lodoxamide (lodoxamine), nedocromil, olopatadine, or pemirolast).If xerophthalmia is associated with infective bacterial disease (a kind of like this infection of meibomian gland or corneal infection); by collyrium and a kind of formulated in combination product or it is given with formulated in combination product form, these formulated in combination product can comprise suitable antibiotic (for example ciprofloxacin, erythromycin, gentamycin, ofloxacin, sulfacetamide, tobramycin or single ofloxacin (monofloxacin)) so.If xerophthalmia is associated with viral infection, so by collyrium and a kind of formulated in combination product or it is given with formulated in combination product form, these formulated in combination product have a kind of antiviral agent, for example trifluridine or idoxuridine.

Another example of therapeutic alliance is such experimenter, after presenting rubescent eyes (irritated eyes) and following telangiectatic face red spot, this experimenter be diagnosed as the cutaneous lupus damage that has on face and/or eyes acne erythematosa both.With the collyrium that comprises the compound with Formula I and/or II or be applied to facial local preparation this experimenter is treated, and for example, for example, with oral antibiotic (tetracycline antibiotics, minocycline) this experimenter is treated.Alternately, the topical composition (gel that is for example used for the treatment of DLE) that is used for the treatment of skin LE also comprises a kind of topical agent that is used for the treatment of acne erythematosa, for example Metrogel.

In another example, this experimenter presents cutaneous lupus and the another kind of Autoimmune Disorders being pre-existing in, and treats with the local preparation that comprises the compound with Formula I and/or II.Also use the oral corticosteroid therapy of systematicness (for example) (for example gradually the prednisolone of less dosage) to treat this experimenter.

Example 11

Local application's device and dosage form

Compositions of the present invention can be used in an application device, this application device allows by the target site of said composition application to skin and not by the non-target site region of said composition application to skin.For example, can adopt a kind of like this device, this device allows said composition to use, and does not first apply it on people's finger.Applicable device comprises spatula, cotton swab, not with syringe and the adhesive patch of syringe needle.Use spatula or cotton swab or analog can need this device to inject in the container that comprises said composition.Using syringe or adhesive patch to be accompanied by is full of this syringe or patch by said composition.Then said composition can be carried out to part by spatula or cotton swab and send out, or it is discharged to from syringe on people's skin.

In one embodiment of the invention, by the compositions that comprises this compound and reinforcing agent, the form with a kind of adhesive patch provides.Some examples of adhesive patch are known.For example,, referring to U.S. Patent number Des.10296,006; 6,010,715; 5,591,767; 5,008,110; 5,683,712; 5,948,433; And 5,965,154.Such patch has an adhesive layer of using the skin of the pure man conventionally, for preserving storage (depot) or the deposit (reservoir) of this pharmaceutical agent and stoping medicine from the outer surface of this storage seepage.The outer surface of patch is inviscid typically.

According to the present invention, the compound that is used for the treatment of cutaneous lupus is merged in this patch, makes this compound keep the stable period that continues prolongation.Compound can be incorporated in polymeric matrix, this polymeric matrix makes it stablize and allow this compound to fill the air from substrate and patch.Compound can also be incorporated to the adhesive layer of patch, once make like this this patch application to skin, this compound can fill the air to skin or even enter or see through skin.According to such an embodiment, as disclosed in this, sticky agent preferably includes a kind of reinforcing agent.In one embodiment, can be by this adhesive layer heat-activated, the temperature of approximately 37 degrees Celsius causes this sticky agent slowly to liquefy thus, make this compound fill the air from this patch and to skin, enter skin or see through skin.When storing under lower than 37 degrees Celsius, this sticky agent can keep being clamminess, once and application to skin, because its liquefaction, this binding agent loses its viscosity.Once this patch no longer adheres to skin, the completing of this compound.

Alternately, this compound can be provided in one or more holes or pocket of the near surface that is placed in patch, this patch will with contact skin.In one embodiment, this compound is stored in the hole in dry or lyophilised state.Such patch is stored in to the stability that for example, maintains this compound in cooling atmosphere (, approximately 4 degrees Celsius).While needing, patch can be shifted out from cooling atmosphere, and apply it to people's skin, wherein, when for example, mixing with fluid (water or saline), can make this compound dissolution.This fluid can separately be provided or be provided as the component of this patch.For example, fluid can be provided on people's skin, make when the patch that comprises dry compound and this fluid interaction, this compound is exposed to this fluid and dissolved.Then, the compound of dissolving can be absorbed by the skin.As another example, this patch can comprise one or more for retain hole or the pocket of fluid at this patch.Can force this fluid from these holes or pocket, to flow out to cause this fluid and this dry compound.For example, this fluid can be provided in a pocket of this patch, and comprises in certain embodiments a kind of for strengthening or activate the reagent of this compound.This patch is exerted pressure, cause this pocket to break and discharge this fluid, make it and this dry compound.Therefore the compositions that comprises this compound can fill the air this patch.In another example, fluid (gel or the emulsifiable paste that for example comprise water) can be applied to the skin of target site.Then will comprise the patch application to skin of dry compound, wherein this fluid and this compound and said composition shift out and move on skin from this patch.

In the patch in the hole that comprises dry compound, these holes seal, and this compound are retained in hole until this compound is given.Therefore, with film (membrane or film), by these hole sealings, this tunic stops this compound to fill the air from these holes in the drying regime of this compound, but when it is dissolved, allows this compound to fill the air from these holes.This tunic can be porous also or atresia.In one embodiment, this tunic comprises cellulose or starch, and more specifically, this tunic can comprise polyvinyl alcohol, polyethylene glycol oxide and hydroxypropyl emthylcellulose.This tunic is thin (thickness range from approximately 1 μ m to about 1mm) and dissolve when contact liq.Therefore the fluid that, is positioned over gel in application on human skin or emulsifiable paste or the pocket from patch and derives can contact and cause this film dissolving with cellulose membrane.After dissolving, this fluid and this dry compound and dissolve this compound.Then, said composition fills the air this patch and to experimenter's skin.

Extraly, this transdermal patch can comprise a plurality of small pinheads, and these small pinheads extend through horny layer, but not extending into corium makes angiorrhexis.When extend on the corium surface from this patch, the length of these syringe needles can be between 20 μ m and 1mm.Therefore, these syringe needles extend through horny layer, but stop before the corium at capillary bed place.These syringe needles can be solid or hollow.The syringe needle of hollow can have a chamber, and this chamber extends along its length, makes said composition to pass the end that enters the syringe needle in epidermis by the storage from this patch.Can allow said composition to fill the air along the outer surface that enters the syringe needle in epidermis with solid syringe needle.

Use the adhesively target region of application to skin of Shi，Jiang Gai local application device, this target region has one or more cutaneous lupus damages, and this applicator is stayed to original place until the compound in patch is given to skin injury.Local application's device (for example patch) provide this medicine extending the period for example, sustained release in (some hours, or even at least one day or longer).

Example 12

Other dosage forms and additive

This part preparation can be prepared to various ways.Solids normally firm and be not pourable, and be conventionally configured to bar or rod or particulate form; Solids can be opaque or transparent, and can optionally comprise solvent (comprising water and alcohol), emulsifying agent, wetting agent, softening agent, aromatic, dyestuff/coloring agent, antiseptic and active component.Normally mutually similarly, main difference is their viscosity (emulsifiable paste is typically thicker and more tacky than lotion) for emulsifiable paste and lotion; Lotion and emulsifiable paste can be both opaque, transparent or clarification, and conventionally comprise emulsifying agent, solvent (comprising water and alcohol) and viscous regulator.Lotion and emulsifiable paste can also optionally comprise wetting agent and softening agent (especially in the situation of skin nursing products), together with aromatic, dyestuff/coloring agent, antiseptic and active component.Can prepare gel/serosity with a series of viscosity (from thick (high viscosity) to rare (low viscosity)), the main difference of they and lotion and emulsifiable paste is that gel/serosity is normally clarified but not opaque.Be similar to lotion and emulsifiable paste, gel/serosity comprises emulsifying agent, solvent (comprising water and alcohol) and viscous regulator conventionally, and can comprise wetting agent and softening agent, aromatic, dyestuff/coloring agent, antiseptic and active component.Waterborne liquid is rarer than emulsifiable paste, lotion or gel, and normally transparent; Liquid does not comprise emulsifying agent conventionally.Liquid topical product also comprises other solvents except water (comprising alcohol), and can comprise viscous regulator, wetting agent and softening agent, aromatic, dyestuff/coloring agent/pigment, antiseptic and active component.

For the applicable emulsifying agent using at preparation, comprise, but be not limited to: Incroquat Behenyl TMS(mountain Yu base trimethyl ammonium Methylsulfate (behentrimonium methosulfate), cetearyl alcohol); Nonionic emulsifier, picture polyoxyethylene oil alkene ether, PEG-40 stearate, ceteareth-12(for example, the Eumulgin B-1 being manufactured by Henkel Corp. (Henkel)), ceteareth-20(Eumulgin B-2 that for example ，You Henkel Corp. (Henkel) manufactures), ceteareth-30, Lanette O(You Henkel Corp. (Henkel) manufactures; Ceteareth alcohol), tristerin (for example, the Cutina GMS being manufactured by Henkel Corp. (Henkel)), PEG-100 stearate, Arlacel 165(tristerin and PEG-100 stearate), stearyl alcohol polyethers-2 and stearyl alcohol polyethers-20, or its combination/mixture; Together with cationic emulsifier, as SAPDMA and mountain Yu base trimethyl ammonium Methylsulfate (behentrimonium methosulfate), or its combination/mixture.In addition, preferably, cationic emulsifier is merged or is mixed the stable emulsion product that comprises high strontium salinity to form with nonionic emulsifier.

For the applicable secondary activity composition using at these preparations, comprise, but be not limited to: alpha-hydroxy acid, sunscreen, Antiperspirant, anti-acne drug, vitamin (especially vitamin A and C) and mineral, and different prescription and the medicine that does not need prescription to sell.As long as one or more diseases that are suitable for treating can have various active composition in these these disclosed compositionss in same local preparation, and can use the combination (for example listed above those) of active component.

Can in preparation of the present invention, use applicable aromatic and pigment, for example FD& The red No.40 of C and FD& The yellow No.5 of C.Be known in the art and be applicable to the aromatic of topical product and other examples of pigment.

Other applicable supplementary elements and the auxiliary component that can be included in these preparations comprise; but be not limited to: grinding agent, absorbent, anti-caking agent, defoamer, antistatic additive, astringent are (for example; Radix Hamamelidis Mollis, alcohol and herb extracts (for example camomile extract)), binding agent/excipient, buffer agent, chelating agen (for example; Versene EDTA), film forming agent, regulator, emulsifying reagent, pH adjusting agent (for example, citric acid and sodium hydroxide) and protective agent.The example of every kind of these compositions in topical product preparation can be found in cosmetics together with the example of other applicable compositions, toiletry, aromatic community (The Cosmetic, Toiletry, and Fragrance Association(CTFA)) in publication.Referring to, for example, CTFA cosmetic composition handbook (CTFA Cosmetic Ingredient Handbook), the 2nd edition, editor .John A.Wenninger(John A. Wen Nige) and G.N.McEwen(G.N. Mike according to civilian), Jr.(CTFA, 1992).

And, multiple product type (comprising cosmetics) can be mixed with to every kind of form described above (that is, solid, emulsifiable paste, lotion, gel and liquid).For example, cleaning agent (for face and health), shampoo/conditioner, hairdressing gel/hair dye/agent for permanent hair waving/hair straighten, Antiperspirant/deodorizer, cosmetic product and other faces, hand and health product configuration can be become to any of five kinds of major product forms: solid, emulsifiable paste, lotion, gel or liquid.Common solid form product comprises cosmetics (for example lip pomade, rouge and kermes), cosmetic product, Antiperspirant and deodorizer (deodorant stick) and cleaning agent, for example soap slab and detergent.Other examples of solid form product comprise lozenge and the suppository of the cutaneous lupus damage that is used for the treatment of mucosa (for example mouth or anus).Common emulsifiable paste and lotion form product comprise 'alpha '-hydroxy acids (AHA) product, moisturizer (moisturizing product) and sunscreen, shampoo/conditioner and other hair products and cosmetics, as concealer and foundation cream.Common gel products comprises shaving gel and aftershave lotion.Common liquid form product comprises anti-acne solution, aftershave lotion, collutory/collutory and cosmetic water/wrister agent/skin conditioner.

Additive method and material for the preparation of the preparation of various ways are also described in Anthony L.L.Hunting(Anthony L.L. Chinese front yard) (editor), " cosmetic formulations formulary (the 2nd volume)-emulsifiable paste; astringent and emulsion " (" A Formulary of Cosmetic Preparations (Vol.2)--Creams; Lotions and Milks; "), Micelle Press(Micelle publishing house) (England, N.J.1993) in.Referring to, for example, the 7th chapter, pp.5-14(oil and gel); The 8th chapter, pp.15-98(substrate and emulsion); The 9th chapter, pp.101-120(" universal product "); The 10th chapter, pp.121-184(purifies mask, emulsifiable paste, lotion); Chapter 11, pp.185-208(foundation cream, vanishing cream (vanishing) and day cream); The 12nd chapter, pp.209-254(emollient); The 13rd chapter, pp.297-324(facial-care product); The 14th chapter, pp.325-380(hand product); The 15th chapter, pp.381-460(health and skin cream and lotion); And the 16th chapter, pp.461-484(baby products); Its content is combined in to this by reference.

Example 12

Exemplary local preparation

Can prepare the local preparation of multiple advantage and use multiple excipient concentration as the described herein.Table 2 is inventories of the excipient that uses in this example, and is not limited to the function of any concrete theory, every kind of excipient.

Table 3

Excipient inventory and function thereof

Reference table 3, the PEG400 Shi Cong standing grain major company (Croda Inc.) adopting in processing instance, Edison (Edison), the commercially available super refining PEG400 in New Jersey (Super Refined Polyethylene Glycol400).Similarly, also obtainable super refining isosorbide dimethyl ether (Super Refined dimethyl isosorbide) is (DMI) in these examples, typically to use Liao Cong standing grain major company (Croda Inc.).

In order to prepare these preparations, in a glass container, add excipient and Compound I, and at 65 ℃ to 70 ℃ heating and/or sonication so that API dissolve completely.Then this sample is cooled to room temperature.Composition for the exemplary preparation prepared by this method is recited in following table 4 and 5.

Table 4

Component	Grade	% by weight	Weight (g)/kg
				Compound I	GMP	3.0	30
Super refining PEG400	NF	39.95	399.5
				Polyethylene Glycol 4500	NF	32.0	320
Butylated hydroxytoluene, granule	NF	1.0	10
				MYRJ?S100-PA-SG	--	5.0	50
Super refining isosorbide dimethyl ether	--	15.0	150
				Purify waste water	USP	4.0	40
Caramel	NF	0.05	0.5
				?	Amount to	100	1000

Table 5

Component	Grade	% by weight	Weight (g)/kg
				Compound I	GMP	6.0	60

Super refining PEG400	NF	33.95	339.5
				Polyethylene Glycol 4500	NF	35.0	350
Butylated hydroxytoluene, granule	NF	1.0	10
				MYRJ?S100-PA-SG	--	5.0	50
Super refining isosorbide dimethyl ether	--	15.0	150
				Purify waste water	USP	4.0	40
Caramel	NF	0.05	0.5
				?	Amount to	100	1000

Claims (25)

1. treat a method for cutaneous lupus, the method comprises that experimenter that Xiang Yiwei suffers from cutaneous lupus gives the compound with Formula I and/or II or its pharmaceutically acceptable salt form of an effective dose partly

2. the method for claim 1, wherein this experimenter suffers from cutaneous lupus damage, and this compound is applied in these cutaneous lupus damages partly.

3. method as claimed in claim 2, wherein this experimenter suffers from ACLE, subacute lupus erythematosus, chronic skin lupus erythematosus or Drug lupus erythematosus.

4. method as claimed in claim 3, wherein this experimenter suffers from ACLE or subacute lupus erythematosus.

5. method as claimed in claim 3, wherein this experimenter suffers from the imbalance of chronic skin lupus.

6. method as claimed in claim 5, wherein this chronic skin lupus imbalance is discoid lupus erythematosus, chilblain lupus erythematosus, lupus erythematosus lichen planus overlap syndrome, lupus erythematosus panniculitis, lupus erythematosus tumidus or excipuliform lupus erythematosus.

7. method as claimed in claim 6, wherein this discoid lupus erythematosus is child's discoid lupus erythematosus, extensive discoid lupus erythematosus or limitation discoid lupus erythematosus.

8. method as claimed in claim 2, wherein this cutaneous lupus comprises the place's skin injury being associated with Drug lupus erythematosus.

9. method as claimed in claim 2, wherein this compound also to this experimenter's general give and give this treatment cutaneous lupus.

10. the method for claim 1, the salt that wherein this its pharmaceutically acceptable salt form is a kind of Compound I I.

11. methods as claimed in claim 10, wherein the salt of this Compound I I is to be selected from sodium salt, potassium salt, calcium salt, arginine salt and choline salt.

12. the method for claim 1, wherein the compound of this Formula I and/or II or its pharmaceutically acceptable salt form jointly also or auxiliarily give with a kind of anti-inflammatory drug, antihistamine drug, antibiotic medicine or antiviral drugs.

13. 1 kinds of preparations, comprise Compound I and/or Compound I I, and wherein this preparation is a kind of topical formulations.

14. medicament preparations as claimed in claim 13, wherein this topical formulations comprises a kind of solution, gel, ointment, emulsifiable paste or suspension.

15. medicament preparations as claimed in claim 13, wherein this topical formulations comprises a sticky agent applicator

16. 1 kinds of treatments suffer from the experimenter's of chronic skin lupus erythematosus method, and the method comprises the compound with Formula I and/or II that gives an effective dose to this experimenter, or its pharmaceutically acceptable salt form

17. methods as claimed in claim 16, wherein this experimenter suffers from ACLE, subacute lupus erythematosus or chronic skin lupus erythematosus.

18. methods as claimed in claim 17, wherein this experimenter suffers from ACLE or subacute lupus erythematosus.

19. methods as claimed in claim 17, wherein this experimenter suffers from the imbalance of chronic skin lupus.

20. methods as claimed in claim 19, wherein this chronic skin lupus imbalance is discoid lupus erythematosus, chilblain lupus erythematosus, lupus erythematosus lichen planus overlap syndrome, lupus erythematosus panniculitis, lupus erythematosus tumidus or excipuliform lupus erythematosus.

21. methods as claimed in claim 20, wherein this chronic skin lupus imbalance is discoid lupus erythematosus.

22. methods as claimed in claim 21, wherein this experimenter does not suffer from systemic lupus erythematosus (sle) and does not have Anti-DNA antibody.

23. methods as claimed in claim 22, wherein this experimenter does not have anti-dsDNA antibody.

24. 1 kinds of medicine boxs that comprise medicament preparation, this medicament preparation comprises Compound I and/or Compound I I or its pharmaceutically acceptable salt form, this medicine box is for giving this medicament preparation to skin

25. Compound I and/or Compound I I or its pharmaceutically acceptable salt form are for the purposes of the topical therapeutic of cutaneous lupus

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